Lecture outline…

Know the:

1.Urea Cycle: Reaction and Significance.

2.The Importance of the Cytosol and Mitochondria.
3.Enzyme Defect and Subsequent Clinical Diagnosis.
 Learning Objectives
II.Urea Cycle

A.Reactions of the urea cycle.

1.Synthesis of carbamoyl phosphate.
2. Production of arginine by urea cycle.
3. Cleavage of arginine to produce urea.

 B. Origin of ornithine.

 C. Regulation of the urea cycle.

 D. Function of the urea cycle during fasting.

III. Disorders of the Urea Cycle.

http://www.wiley.com/college/fob/quiz/quiz20/20-8.html
 What is Urea
 Urea is a diamide, chief nitrogenous waste
product.
O

H2N C NH2
Urea

What are the Precursors of Urea

 Ammonia +CO2 + Aspartate are the precursors
of Urea.

Other nitrogenous waste products which includes

uric acid & creatinine.
Summary of Amino Acid Metabolism
Dietary Proteins
Digestion (Stomach Intestine)
Amino Acids in Blood
Membrane
Other
Proteins Amino Acids N-Containing
Compounds

Carbon Nitrogen
γ -Aminobutyrate
Dopamine
Norepinephrine
O Epinephrine
CO2 + H2O H2N-C-NH2 Serotonin

Energy ATP Urea

 Fate of Amino Acid Nitrogen: Urea Cycle
Amino Acids
Carbon Storage
Nitrogen

CO2+H2O
NH4+ Energy
COO- +CO2
ATP
-

H C- NH2
-
O
-

COO- Urea NH2 -C- NH2

Aspartate Cycle Urea

What are the source of amino groups and carbonyl group for
the biosynthesis of Urea?.
Excretion of Nitogenous Waste Products
The carbon chains are
Amino acids broken down to molecules
Most mammals convert that feed into the TCA
amino-acid nitrogen to cycle.
urea for excretion NH4+
Some animals
excrete NH4+ or
uric acid.

Most terrestrial Fish & other

aquatic Birds & reptiles
vertebrates
vertebrates

O
H
O HN N
NH4+ Uric O
H2N-C-NH2
Ammonium acid O N N
Urea ion H H
An Overview of Urea Cycle

What Are The Sites & The

Organ In Which Biosynthesis
Of Urea Occurs?

 Urea biosynthesis occurs partly

in the cytosol and partly in the
mitochondria of the liver.

Net reaction:
NH3+ CO2 + 2 ATP Carbamoyl-Phosphate
+
(HCO3)
2 ADP + Pi
Mitochondrial The Urea Cycle in the Liver
Matrix
NH4+ + HCO3- + 2 ATP
Carbamoyl 1
phosphate synthase I (CPS-I)
Carbamoyl phosphate

Ornithine 2
Transcarbamoylase (OTC) Ornithine
Hepatocyte

Citrulline

Citrulline Aspartate
Argininosuccinate Ornithine
ATP
Synthetase 3
AMP+ Pi
Argininosuccinate
Argininosuccinate 5
4 Fumerate
Lyase Arginase

Arginine
Cytoplasm Urea
 What is Normal Value of Urea
 Serum urea concentration is 15-40 mg/dL.

 Accumulation of urea more than normal value in

blood is referred as’
as ”Uremia”.

 Urea Excretion: 20–30 gm / day.

Is there any Specific functions of Urea

 Not yet identified, but probably may involve in
‘’’’’the maintenance of osmotic balance as a
‘’’’’crystalloid.
 Osmolality of Plasma
Osmolality is a measure of the solute particles
present in the fluid medium.
Osmolality of Plasma: 285-295 milliosmoles / Kg.

Plasma Osmolality can be computed from the

concentrations (mmol/l) of Na+, K+, urea, & glucose
as follows.
2(Na+) + 2(K+) + Urea + Glucose
The factor 2 is used for Na+ & K+ ions for the
associated anion concentration.
Plasma Osmolality will be altered in lipidaemias, ESRD,
hyperproteinaemia, ketoacidosis, diabetes insipidus,chronic
alcohol intoxication, diuretics & in chronic diarrhoea.
 Is any Clinical Conditions Are
related with Low Urea Level
 Impairment of liver functions and congenital
deficiencies of urea cycle enzymes will impair the
biosynthesis of urea, which ultimately leads to
accumulation of ammonia in blood and CSF causes
“azotemia”.
 What Is Meant By Azotemia
 Accumulation of nitrogenous materials including
ammonia due to impairment in urea biosynthesis
due to,

 Urea cycle enzyme deficiencies,

 Gastrointestinal tract (GI) bleeding,

 Valproic acid therapy and

 Renal impairments ect.,.

What Are The Consequences of Uremia
 Uremia will leads to ammonia toxicity,
hypercapnia & alkalosis which may leads to
neurotoxicity depending on the severity.

 Impaired renal function leads to erythropoietin

deficiency and hence accumulation of CO2.
What Are The Causes of Uremia

 Ureamia may occur as a result of impairment in

‘’’’’the renal functions, which occur as a result of

 nephrotic syndrome,

 heavy metal toxicities,

 ESRD and

 nitrogen load due to high protein diet.

 Importance of Urea Cycle

 Removal of CO2.

 Removal of Ammonia.
 Recycling of TCA cycle intermediates.
 Recycling of amino acids & ketoacids.
Involvement of Peripheral Tissues And Liver in the
Ammonia Metabolism

α-KG = α-Ketoglutaratee
GDH = Glutamate Dehydrogenase.
Molecualr Interconversions in Handling of Ammonia
Alanine α-Ketoglutarate Aspartate

NH4+
NADH+H+
ALT
NADPH+H+ Glutamate AST
NADPH + Dehydrogenase
Pyruvate
H2O NAD

Glutamate Oxaloacetate

NH4+
Glutamine ATP
Synthetase
ADP+Pi

Glutamine

The major enzyme responsible for the interconversion of Glutamate into α-KG
is
Glutamate Dehydrogenase. ALT= Alanine aminotransferase
Reactions of the Urea Cycle

1. Synthesis of Carbomoyl Phosphate.

2. Production of Arginine by the Urea Cycle.
3. Cleavage of Arginine to Produce Urea.
 O

H2N C NH2
Urea

 Most terrestrial land animals convert

excess nitrogen to urea, prior to excreting it.
 Urea is less toxic than ammonia.
 The Urea Cycle occurs mainly in liver.
 The 2 nitrogen atoms of urea derived from
NH3 and the amino nitrogen of aspartate.
 HCO3− + NH3 + 2 ATP
Carbamoyl Phosphate
Synthase-I
O

H2N C OPO32− + 2 ADP + Pi

Carbamoyl phosphate

Carbamoyl Phosphate Synthase is the committed step of the Urea

Cycle, and is subject to regulation.

The NH3 and HCO3- that will be part of urea are incorporated first
into carbamoyl phosphate (CP).
 Glutamate (Glu) N-Acetylglutamate
H O H
H3 N+ C COO− H3C C N C COO−
H
CH2 CH2
CH2 CH2
COO− COO−

Carbamoyl Phosphate Synthase-I has an absolute

requirement for an allosteric activator
N-acetylglutamate.
This derivative of glutamate is synthesized from
acetyl-CoA & glutamate when cellular [glutamate] is
high, signaling an excess of free amino acids due to
protein breakdown or dietary intake.
Formation & Degradation of N-Acetylglutamate
(NAG)

NAG NAG

 N-Acetyl glucoseamine (NAG) serves as an allosteric

activator for the enzyme CPS-I for the biosynthesis of
carbamoyl phosphate (CP) with the help of HCO3- and ATP.

 NAG, is an allosteric activator of CPS-I.

The Reactions
Mitochondria
of the Urea
Cycle

NAG:N-acetyl
glutamate; (in the Cytosol
formation of urea, *
one amino group is
derived from free
NH4+ ion, while the
other is from NAG
aspartate. Carbon is *
obtained from CO2.
(*) mitochondrial
enzymes, the rest
of the enzymes are
cytosolic).
Role of Glutamate in Urea Production
Amino acids α-Ketoglutarate

Transamination Other reactions

Glutamate
α-Ketoacids

Transamination
α-Ketoglutarate Oxalaoacetate
NH4+

Aspartate
Urea
Cycle
Urea
Role of Glutamate in Amino Acid Synthesis
α-Ketoglutarate

Transamination PLP GDH

Glutamate
α-Ketoacid
PLP
Amino acids

α-Ketoglutarate
Glutamate transfers Nitrogen by means of transamination
reactions to α–ketoacids to form AAs. The nitrogen is
obtained by glutamate either from transamination of other
AAs or from NH4+ by means of the glutamate dehydrogenase
 COO− COO−

COO− CH2 COO− CH2

CH2 CH2 CH2 CH2

HC NH3+ + C O C O + HC NH3+

COO− COO− COO− COO−

Aspartate α-Ketoglutarate Oxaloacetate Glutamate

Aminotransferase (Transaminase)

Oxaloacetate is converted to aspartate via

transamination (e.g., from glutamate).
Aspartate then reenters Urea Cycle, carrying an amino
group derived from another amino acid.
Regulation of the Urea Cycle
 Liver has a vast capacity to convert AA nitrogen to urea
,thereby preventing toxic effects from ammonia.

 Urea cycle is regulated by substrate (S) availability;

the higher the rate of NH3 production, the higher the
rate of urea formation.

 Regulation by the S availability is a general

characteristics of disposal pathways, such as the urea
cycle, which remove toxic compounds from the body.

 This is a type of “feed-forward” regulation, in contrast

to the “feed-back” regulation characteristic of
pathways that produce functional endproducts.
Regulation of the Urea Cycle…
 The other type of regulation control the urea cycle:
Allosteric activation of CPS-I by N-acetylglutamate
(NAG) and induction/repression of the synthesis of urea
cycle enzymes.

 NAG is formed specifically to activate CPS-I; it has no

other known function in mammals.

 The synthesis of NAG from acetyl CoA and glutamate is

stimulated by arginine.

 Thus, the arginine level increase within the liver, 2

important reactions are stimulated.

 The first is the synthesis of NAG, which will increase

the rate at which CP is produced.

 nd
D. Functions of Urea Cycle During Fasting
 During fasting, the liver maintains blood glucose by
gluconeogenesis by utilizing muscle protein AAs as a
carbon source.

 As AA carbons are converted to glucose, the nitrogens

are converted to urea, thus the urinary excretion of
urea is high during fasting.

 As fasting progresses, the brain begins to use ketone

bodies, sparing blood glucose.

 Less muscle protein is cleaved to provide AAs for

gluconeogenesis,and decreased production of glucose
from AAs for gluconeogenesis.

 Hence, Decreased production of glucose from AAs is

accompanied by decreased production of urea.
D.Functions of Urea Cycle During Fasting…
 The major AA substrate for gluconeogenesis is Alanine,
which is synthesized in peripheral tissues to act as a
nitrogen carrier.

 Glucagon release, which is expected during fasting,

stimulates alanine transport into the liver by activating
the transcription of transport systems for alanine.

 Two molecules of alanine are required to generate one

molecule of glucose.

 The nitrogen from 2 molecules of alanine is converted to

one molecule of urea.
 Hereditary deficiency of any of the Urea Cycle
enzymes leads to hyperammonemia - elevated
[ammonia] in blood.
 Total lack of any Urea Cycle enzyme is lethal.
 Elevated ammonia is toxic, especially to the brain.
 If not treated immediately after birth, severe
mental retardation results.
 Genetic Deficiency of Urea Synthesis
May be caused by,

1. Ornithine Transcarbamylase Deficiency (OTC)

2. Citrullinemia.
3. Arginase Deficiency
4. Argininosuccinic Aciduria
5. Carbamyl Phosphate Synthetase (CPS-I) Deficiency
6. N-Acetyl Glutamate Synthetase Deficiency (NAGS)
 Genetic Deficiency of Urea Synthesis

Carbamoyl Phosphate Synthetase-I Ornithine

(CPS-I) Deficiency Transcarbamylase (OTC)

↑[NH4+]; hyperammonemia ↑[NH4+];

hyperammonemia
↑Blood Glutamine ↑Blood Glutamine
BUN is decreased BUN is decreased
No increase in uracil or orotic acid ↑Uracil & orotic acid in
blood & urine
Cerbral edema Cerebral edema
Lethargy, convulsions, coma, death Lethargy, convulsions,
coma, death
 Metabolic Diseases of the Urea Cycle

Disorders present in infants:

Symptoms: Lethargy, swelling of the brain leads to mental

retardation / brain damage.

Diagnosis: Low blood urea nitrogen (BUN) levels -high levels

of ammonia in the blood elevated circulating glutamine
-other metabolites that accumulate depend on the specific
enzyme defect.

Most common form: Hyperammonemia Type II caused by

Ornithine Transcarbamylase (OTC) Deficiency elevated
Carbamoyl-Phosphate (CP) levels in this deficiency cause
secondary problems in pyrimidine metabolism.
Treatment:

Long term, dietary restriction.

Low protein diet. Supplemented with Arginine.

Short term
Dialysis.
Administration of Nitrogen “scavengers”.
e.g. Phenylacetate.
 Treatment of Hyperammonemia with Phenylacetate:
taking advantage of metabolism

Phenylbutyrate
Glycine + Benzoic Acid Hippuric Acid

Excreted in Urine
Transaminases Anemia Folate
Deficiencies / Genetics
Urea Cycle + Modulators
Cofactors
Protein Degradation Alllosteric inhibitors
Nutritional Deficiencies
Heme & Biliribin
Allopurinol Signs & Symptoms
PKU

Sulphur End pdt accumulation Treatment /

Management.
Tyrosine Cofactors required

Purines Lead

Pyrimidines
HGPRT
Anticancer Drugs
Albinism
Gout

Enzyme deficiencies
1. The rate-limiting step in the urea biosynthetic pathway is
Catalyzed by the enzyme,
A. Carbamoyl phosphate synthetase-I (CPS-I)
B. Ornithine transcarbamoyl trasferase (OTC)
C. Argininosuccinate synthase.
D. Argininosuccinate lyase.
E. Arginase.

Answer: A. The rate-limiting step (committed step) in the urea

biosynthetic pathway is catalyzed by the enzyme carbamoyl
phosphate synthase-I (CPS-I).

?
Which biomolecule acts as a positive modulator for the first
tep of the urea cycle which is catalyzed by carbamoyl
hosphate synthetase-I (CPS-I).

. Gultamate.
. Glutamine.
. N-Acetyl Glutamate (NAG).
. Aspartate.
. Ammonium ions (NH4+).

nswer: C. N-Acetyl glutamate acts as a positive modulator for

e first step of the urea cycle which is catalyzed by CPS-I.
he

?
. Two days after a full-term normal delivery, a neonate begins
o hyperventilate, develops hypothermia and cerebral edema,
nd becomes comatose. Urinalysis reveals high levels of
lutamine and orotic acid. The BUN is below normal. Which
nzyme is most likely to be deficient in this child?.

. Cytoplasmic glutaminase.
. Cytoplasmic carbamoyl phosphate synthetase.
. Cytoplasmic orotidylate decarboxylase.
. Mitochondrial carbamoyl phosphate synthetase.
. Mitochondrial ornitihine transcarbamoylase.

nswer: E. Given these symptoms, the defect in the urea cycle

nd the elevated orotate suggests deficiency of ornithine
anscarbamoylase (OTC).

?
19.2. Which one of the following statements about the urea cycle
is correct?

A. The two nitrogen atoms that are incorporated into urea enter
the cycle as ammonia and alanine.
B. Urea is produced directly by the hydrolysis of ornithine.
C. ATP is required for the reaction in which argininosuccinate is
cleaved to form arginine.
D. Urinary urea is increased by a diet rich in protein.
E. The urea cycle occurs exclusively in the cytosol.

Correct answer = D. The amino nitrogen of dietary protein is

excreted as urea. The two nitrogens enter the urea cycle as
ammonia and aspartate. Urea is produced by the hydrolysis of
arginine. The cleavage of argininosuccinate does not require
ATP. The urea cycle occurs partly in the mitochondria.
?
Transamination reactions are essential for ammonia assimilation.
What cofactor is required to catalyze transamination reactions?
A. pyridoxal phosphate (PLP)
B. thiamin pyrophosphate
C. biotin
D. NAD+
E. NADPH
Ans: A.
Which of the following enzymes function in the biological
assimilation of ammonia?.

A. glutamate dehydrogenase.
B. glutamine synthetase.
C. glutamate synthase.
D. all of the above.

Ans: D.

?
Which of the following protein modifications target a protein for
degradation?.

A. Phosphorylation.
B. Ubiquitination.
C. Zymogen activation.
D. Subunit aggregation.
E. All of the above.

Ans: B.

?
Specific amino acids associated with the ______ of
a protein
determine its half life.

A. C-terminal.
B. N-terminal.
C. All of the above.

Ans: B. (N-terminal / amino terminal).

?
Ubiquitin is covalently attached to a protein through
an amide linkage to which specific amino acid?.

A. Aspartate.
B. Glutamate.
C. Lysine.
D. Arginine.
E. Histidine.

Ans: C.

?
What part of the 26S proteosome complex recognizes an
ubiquitinated protein?.

A. 20S proteosome core.

B. 19S cap.
C. E3 subunit.
D. E2 subunit.
E. All of the above.

Ans: B.

?
In a patient with cystic fibrosis, the mutant cytosolic
transmembrane conductance regulator (CFTR) protein folds
incorrectly. The patients cells modify this abnormal proteins by
attaching ubiquitin molecules to it. What is the fate of this modified
CFTR protein?.

A. It performs its normal function, as the ubiquitin largely corrects

for the effect of the mutation.
B. It is secreted from the cell.
C. It is placed into storage vesicles.
D. It is degraded by the proteasome.
E. It is repaired by cellular enzymes.

Ans: D. Ubiquitination usually marks old, damaged, or misfolded

proteins for destruction by proteasome. There is no known cellular
mechanism for repair of damaged proteins.

?
A young boy has cystic fibrosis, which is due to a mutation
resulting in misfolded protein. The protein is degraded very quickly
inside the cell. This protein degradation is most probably
undertaken by:

A. lipoic acid.
B. acetyl CoA.
C. ubiquitin.
E. linoleoic acid.
E. linolenic acid.

Ans: C.

?
After proteins are synthesized, their lifespan is regulated by
proteolytic degradation. Some proteins are degraded by
lysosomal enzymes. The process of _________ allows
subcellular material, including organelles, to be enclosed by a
membrane and subjected to lysosomal action.

A. autophagy.
B. phylogeny.
C. phagocytosis.
D. pinocytosis.
E. exocytosis.

Ans: C.

?
What part of the 26S proteosome complex contains the
protease function?.

A. 26S proteosome core.

B. 19S cap.
C. E3 subunit.
D. E2 subunit.
E. All of the above.

Ans: A.

?
What is the fate of excess amino acids in animals and humans?.

A. they are recycled for the synthesis of new proteins.

B. they are stored for future use.
C. they are catabolized to free ammonia and carbon skeletons.
D. a and b.
E. a and c.

Ans: C.

?
Fish dispose of toxic ammonia by ___________.

A. converting it to uric acid, which is subsequently secreted.

B. converting it to urea, which is subsequently secreted.
C. releasing it directly to the environment.
D. all of the above.
E. none of the above.

Ans: C.

?
The enzyme of the urea cycle are localized within __________.

A. the mitochondria..
B. the cytosol.
C. the chloroplast.
D. a and b.
E. all of the above.

Ans: D.

?
Which amino acid participates as a pathway intermediate in the
rea cycle?.
urea

A. Lysine.
B. Arginine.
C. Glutamine.
D. Histidine.
E. Tyrosine.

Ans: B.

?
In humans, the urea cycle functions primarily in the ___________.

A. muscle tissue.
B. heart.
C. brain.
D. liver.
E. adipose tissue.

Ans: D.

?
Muscle tissue gets rid of toxic ammonia _________________.

A. by running the urea cycle in its cells.

B. through the glucose / alanine cycle.
C. through the Cori cycle.
D. through the Bohr Effect.
E. none of the above.

Ans: B.

?
A patient presents with Hemolytic Anemia. Which of the following
should be elevated in the BLOOD?.

A. Bilirubin
B. Ammonia
C. Urea
D. Mitochondria
E. Ribose

Ans: A.

?
Your patient is a 60-year-old male who has a long history of
alcohol abuse. He is confused, has an enlarged liver, and a
flapping tremor at the wrist (asterixis). Your diagnosis is hepatic
encephalopathy. A treatment is a diet of branched-chain amino
acids. Which one of the following sets of amino acids is
composed of branched-chain amino acids?.

A. Methionine, proline, and cysteine.

B. Glycine, alanine, and serine.
C. Valine, leucine, isoleucine.
D. Aspartate, glutamate, and asparagine.
E. Tryptophan, phenylalanine, and tyrosine.

Ans: C. Only valine, leucine, and isoleucine compose the only

set of branched-chain amino acids.

?
 A 49-year-old man with a rare recessive condition is at high
sk deep vein thrombosis and stroke and has had replacement
ectopic lenses. He has a normal hematocrit and no
vidence of megaloblastic anemia.

mutation in the gene encoding which of the following is

ost likely to cause this disease?.

Cystathionine synthase.
Homocysteine methyltransferase. XXX
Fibrillin.
Lysyl oxidase.
?
Branched chain α-ketoacid dehydrogenase.

nswer: A. Homocysteine, the substrate for enzyme, accumulates

creasing the risk of deep thrombosis and disrupting the normal
osslinking of fibrillin. Deficiency of homocysteine
ethyltransferase would cause homocysteineuria, but would also
edispose to megaloblastic anemia.
Have a
Break
. A-56-year-old man with a history of genetic disease undergoes
p replacement surgery for arthritis. During the operation the
urgeon notes a dark pigmentation (ochronosis) in the man’s
artilage. His ochronotic arthritis is most likely caused by oxidation
nd polymerization of excess tissue

. Homogentisic acid.
. Orotic acid.
. Methylmalonic acid.
. Uric acid.
. Ascorbic acid.

nswer: A. Adults with alkaptonuria show a high prevalence of

chronotic arthritis due to deficiency of homogentisate oxidase.

?
 A woman 7 months pregnant with her first child develops anemia.
boratory evaluation indicates an increased mean cell volume
MCV), hypersegmented neutrophils, and altered morphology of
veral other cell types. The most likely underlying cause of this
everal
oman’s anemia is,

Folate deficiency.
Iron deficiency.
Glucose-6-phosphate dehydrogenase deficiency.
Cyanocabalamin (vitamin B12 ) deficiency.
Lead poisoning.

nswer: A. Pregnant woman with megaloblastic anemia and

evated serum homocysteine strongly suggest folate deficiency.
on deficiency presents as microcytic, hypochromic anemia and
ould not elevate homocysteine. B12 deficiency is not most
this presentation.
?
 . A 62-year-old man being treated for tuberculosis develops a
icrocytic, hypochromic anemia. Ferritin levels are increased, and
microcytic,
arked sideroblastosis is present. A decrease in which of the
marked
llowing enzyme activities is most directly responsible for the
ollowing
nemia in this man?.

. Cytochrome oxidase.
. Cytochrome P450 oxidase.
. Pyruvate kinase.
. δ-aminolevulinate synthase.
. Lysyl oxidase.

nswer: D. Sideroblastic anemia in a person being treated for

uberculosis (with isoniazid) is most likely due to vitamin B6
eficiency. δ-Aminolevulinate synthase, the first enzyme in heme
ynthesis, requires vitamin B6 (pyridoxine).
?
 . Patients with Lesch-Nyhan syndrome have hyperuricemia,
dicating an increased biosynthesis of purine nucleotides, and
arkedly decreased levels of hypoxanthine phosphoribosyl
markedly
ansferase (HPRT). The hyperuricemia can be explained on the
asis of a decrease in which regulator of purine biosynthesis?.

. ATP.
. GDP.
. Glutamine.
. IMP.
. PRPP.

nswer: D. IMP is a feedback inhibitor of PRPP amidophospho-

ibosyl transferase, the first reaction in the biosynthesis of purines.
MP is formed by the HPRT reaction in the salvage of hypoxanthine.

?
. A 12-week-old infant with a history of persistent diarrhea and
andidiasis is seen for a respiratory tract infection with
neumocystis carinii. A chest X-ray confirms pneumonia and
eveals absence of a thymic shadow. The IgG is present in his
erum, but IgA and IgM are absent. His RBCs completely lack an
ssential enzyme in purine degradation. The product normally
rmed by this enzyme is,
ormed

. Guanine monophosphate.
. Hypoxanthine.
. Inosine.
?
. Xanthine.
. Xanthine monophosphate.

nswer: C. The child most likely has severe combined immuno-

deficiencye caused by adenosine deaminase (ADA) deficiency.
his enzyme deaminates adenosine) a nucleotide) to form inosine
another nucleoside). Hypoxanthine and xanthine are both purine
ases, and the monophosphates are nucleotides..
. In the synthesis of cysteine, the carbon atoms (nearest
recursor) are provided by which of the following?.

. Aspartic acid.
. Methionine.
. Oxaloacetic acid.
. Serine.
. Homocysteine.

nswer: D. This question refers to the precursor of the carbon

toms of cysteine that are provided by serine. Homocystene, a
rect precursor, only supplies sulfur. These two molecules form
ystathionine. Methionine is the precursor to homocysteine.
spartate and oxaloacetate are involved in transamination and do
ot directly affect cysteine synthesis.

?
 Which of the following is the correct enzyme-genetic defect
isease pair?.

. Argininosuccinate synthetase-Citrullinemia.
. Arginase- Argininosuccinate aciduria.
. Ornithine transcarbomylase-Congenital hyperammonemia type-I
. Argininosuccinate lyase-Arginemia.
. Carbamoyl phosphate synthetase-Congental hyperammonemia
type-II.

nswer: A. Defective argininosuccinate synthetase yields

trullinemia. Defective arginase yields mild hyperammonemia.
rnithine transcarbamoylase and carbamoyl phosphate synthetase
eld congenital hyperammonemia type II and I, respectively.
efective argininosuccinate lyase yields hyperammonemia.

?
. Which of the following is a common compound shared by
he TCA cycle and the urea cycle?.

. α-ketoglutarate.
. Succcinyl Coenzyme A (CoA).
. Oxaloacetate.
. Fumarate.
. Arginine.

nswer: D. Fumarate is in both the urea and TCA cycles.

-ketoglutarate, succinyl CoA, and oxaloacetate (OAA) are only in
e TCA cycle. Arginine is only in the urea cycle.
he

?
. Which of the following enzymes requires adenosine
riphosphate (ATP) to mediate its reactions?.

. Argininosuccinate lyase.
. Argininosuccinate synthetase.
. Arginase.
. Glutaminase.
. Ornitine transcarbamoylase.

nswer: B. Argininosuccinate synthetase requires ATP. All of the

her enzymes listed do not require energy and are exergonic
ther
eactions; remember, ∆G is negative.

?
6. Which of the following is the common nitrogen acceptor
for
all reactions involving transaminase?.

A. α-ketoglutarate.
B. α-ketobutyrate.
C. Pyruvate.
D. Oxaloacetate.
E. Acetoacetate.

Answer: A. All transaminases have α-ketoglutarate as the

common nitrogen acceptor. Serine is deaminated to pyruvate, and
threonine is deaminated to α-ketobutyrate. Other amino acids are
converted to acetoacetate.

#124. Slide 12
1. A 55-year-old man suffers from cirrhosis of the liver. Toxins
uch as ammonia are not properly metabolized by the liver and can
ow damage structures such as the brain. Which of the following
mino acids covalently binds ammonia and transports and stores
in a nontoxic form?.
. Aspartate.
. Glutamate.
. Serine.
. Cysteine. ?
. Histidine.

nswer: B. Glutamate and ammonia from glutamine, as catalyzed

y glutamine synthetase at the cost of 1 ATP. Cysteine is not
rectly involved with ammonia. Aspartate and ammonia both
onate a nitogen to form urea (along with ammonia). Histidine and
erine are deaminated, forming ammonia. Central nervous system
ysfunction due to high ammonia-level hepatic encephalopathy
esults in a sequelae of symptoms such as asterixis, confusion and
4. A 2-year-old girl was seen in the emergency room for vomiting
nd tremors. The elevated plasma ammonium ion concentration
as 195 µM (normal, 11-50 µM). Metabolic screens of serum and
rine were ordered and were remarkable for an elevation in the
mino acid arginine in serum. You conclude that this patient may
ave a defect in the following enzymes?.
. Carbamoyl phosphate synthetase I.
. Carbamoyl phosphate synthase II.
. Ornitine transcarbamoylase.
. Arginase. ?
. Argininosuccinate lyase.

nswer: D. This is another case of hyperammonemia. The

esence of elevated arginine indicates that the block is the
resence
onversion to the next step. Arginase converts arginine to
nithine. Argininosuccinate lyase is the step to synthesize to
rnithine.
ginine. Ornithine transcarbamoylase converts ornithine to
rginine.
trulline, and the carbamoyl phosphate synthetases are involved
20.2 Which one of the following statements concerning a one-week-old
male infant with undetected classic phenylketonuria is correct?

A. Tyrosine is a nonessential amino acid for the infant.

B. High levels of phenylpyruvate appear in his urine.
?
C. Therapy must begin within the first year of life.
D. A diet devoid of phenylalanine should be initiated immediately.
E. When the infant reaches adulthood, it is recommended that diet therapy be
discontinued.

Correct answer = B. Phenyllactate, phenylacetate, and phenylpyruvate, which

are not nor-mally produced in significant amounts in the presence of functional
phenylalanine hydroxylase, are elevated in PKU, and appear in the urine. In
patients with PKU, tyrosine cannot be synthesized from phenylalanine and,
hence, becomes essential and must be supplied in the diet. Treatment must
begin during the first seven to ten days of life to prevent mental retardation.
Discontinuance of the phenylalanine-restricted diet before eight years of age is
associated with poor performance on IQ tests. Adult PKU patients show
deterioration of attention and speed of mental processing after discontinuation
of the diet. Life-long restriction of dietary pheny-lalanine is, therefore,
recommended.
20.3 A four-year-old boy of a first-degree consanguineous couple was
noted by the parents to have darkening of the urine to an almost black
color when it was left standing. He had a normal sibling, and there were
no other medical problems. Childhood growth and development were
normal. Which of the following is most likely to elevated in this patient?
A. Methylmalonate
B. Homogentisate
C. Phenylpyruvate
D. α-Ketoisovalerate ?
E. Homocystine

Correct answer = B. Alkaptonuria is a rare metabolic disease involving

a deficiency in homogentisic acid oxidase, and the subsequent
accumulation of homogentisic acid in the urine, which turns dark upon
standing. The elevation of methylmalonate (due to methylmalonyl CoA
mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase
deficiency), α-ketoisovalerate (due to branched-chain α-ketoacid
dehydrogenase deficiency), and homocystine (due to cystathionine
synthase deficiency) are inconsistent with a healthy child with darkening
of the urine.
5. A new test is developed that can non-radioactively “label”
ompounds in the human body. As a physician with a back-ground
n the new field of metabolomics, you assess a 21-year-old with
assical phenylketonuria (PKU). Phenylalanine is fed with a label
the phenyl ring. In the urine, in which of the following compounds
ould you expect to find the greatest amount of label?.
. Tyrosine.
. Tryptophan.
. Epinephrine.
. Phenylketone. ?
. Acetate.

nswer: D. Phenylketonutria (PKU) is a defect in phenylalanine

ydroxylase, resulting in a block in the conversion of phenylalanine
o tyrosine. Phenylalanine accumulates in in both disorders and to
onverted to phenylketones. Tyrosine is the product whose
ormation is blocked, and epinephrine, a product of tyrosine, would
ot be made or “labelled’. Acetate and tryptophan are very far
 The biosynthetic pathway involves both BH4 and a
yridoxal phosphate (PLP)-dependent decarboxylation
eaction to form which of the following?.

. Histamine.
. ‫ﻻ‬-aminobutyric acid (GABA).
. Creatine.
. Epinephrine.
. Carnitine.

nswer: D. Epinephrine synthesis requires both BH4 and a

yridoxal phosphate (PLP)-dependent decaroxylation from
henylalanine→ Tyrosine→DOPA→Dopamine→Epinephrine. Both
istidine→Histamine and Glutamate→‫ﻻ‬-Aminobutyric acid (GABA)
quire pyridoxal phosphate (PLP) for decarboxylation (but not
equire
H4). Creatine is produced from glycine, arginine and S-adenosyl
ethionine (SAM).
. Which of the following is a compound formed from both a
ydroxylation with an enzyme requiring vitamin C and
ubsequent methylation?.

. Histamine.
. Epinephrine.
. GABA.
. Carnitine.
. Creainine.

nswer: B. Epinephrine forms when dopamine is hydroxylated by

n enzyme that requires copper and vitamin C, to form
orepinephrine, which subsequently methylated. Histamine is
erived by decarboxylation of histidine. GABA is decarboxylated
utamate. Creatinine is formed by a SAM methylation, and
arnitine is an acyl group acceptor.

?
Excessive degradation of AMP and GMP would result in
Increased urinary excretion of, ___________.

A. creatine
B. urea
C. uric Acid
D. thiamine
E. thymine

Answer: C. The purine bases, adenine (A) and guaninie (G), are
oxidized to uric acid, which is excreted in the urine. Excessive
Production of uric acid can result in the condition known as gout.

?
Which of the following statement about heme and iron
metabolism is correct?.
?
A. Iron is strored in the liver as transferrin.
B. Iron (as Fe2+ ) is inserted into protoporpyrin IX in the last step.
of heme synthesis
C. δ-ALA synthase catalyzes the regulated and rate-limiting
step in heme biosynthesis.
D. The major route for bilirubin excretion is via the urine.
E. The iron produced by heme degradation is excreted in the feces.
Answer: C. The first rate-limiting step in heme biosynthesis
Involves the condensation of glycine and succinyl CoA to form
Delta-ALA. Iron is stored as ferritin & transported in the blood
in transferrin. As Fe2+ , it is inserted into protoporpyrin IX to form
heme. When heme is degraded to form bilirubin (which is excreted
Mainly via the intestine), iron is returned to the body’s iron stores
and is not excreted. Bleeding is the only significant means by
Which Iron is lost from the body.
 he component that would be elevated to the greatest extent
n the blood of a person suffering from Gout is _________.
. bilirubin.
. uric acid.
. creatine kinase.
. blood urea nitrogen (BUN).
nswer: B.

?
The genetic defect in the hypoxanthine guanine
phosphoribosyl transferse (HGPRT) will leads to,

A. Parkinson’s disease.
B. Cystinuria.
C. Pellagra.
D. Lesch-Nyhan syndrome.
E. Hartnup’s disease.

Answer: D. The defect in the purine salvage enzyme HGPRT

causes Lesch-Nyhan syndrome.

?
 Match the Urea Cycle Disorders With the
Enzyme Defect
No Disorder Answer Enzyme Defect

1 Hyperammonemia type I A. Argininosuccinate synthase

2 Hyperammonemia type II B. Ornithine transcarbomylase (OTC)

3 Citrullinemia C. Argininosuccinate lyase

4 Argininosuccinic Aciduria D. Arginase

5 Hyperargininemia E. Carbamoyl-P synthase-I (CPS-I)

Answer: 1E; 2-B; 3-A; 4-C; 5-D.

?
Genetic Deficiencies in Some of the Urea Cycle Enzymes can
be Treated Pharmacologically by eliminating the amino acids
such as glycine and glutamine by administering,

A. Aspartic acid.
B. Benzoic acid and phenylacetate.
C. GABA.
D. Pyridoxal phosphate.
E. Methionine.

Ans: B. The amide products of these reactions (hippurate and

phenylacetylglutamine) are excreted in the urine. Synthesizing
the Glycine or Glutamine removes ammonia.

?
he reaction catalyzed by glutamate dehydrogenase which
eversibly converts glutamate to α-ketoglutarate require the
ofactor,

. ATP.
. NAD.
. NAD(P)+ / NAD(P)H.
. Biotin.
. Pyridoxal phosphate.

ns: C. The cofactors require by the glutamate dehydrogenase is

AD(P)+ / NAD(P)H.

?
4. Methotrexate is a potent anticancer agent that starves dividing cells of
deoxyribonucleotides through direct inhibition of which of the following
enzymes?

A. Ribonucleotide reductase
B. Xanthine oxidase
C. Carbamoyl phosphate synthetase II
D. Thymidylate synthetase
E. Dihydrofolate reductase ?
F. Adenosine deaminase.

4. The answer is E. Methotrexate is an analog of folic acid that binds

with very high affinity to the substrate-binding site of dihydrofolate
reductase, the enzyme that catalyzes conversion of DHF to THF, which
is used in various forms by enzymes of both the purine and pyrimidine
de novo synthetic pathways. Thus, synthesis of dTMP from dUMP
catalyzed by thymldylate synthetase and several steps in purine
synthesis cat-alyzed by formytransferase are indirectly blocked by the
action of methotrexate because both those enzymes require THF
coenzymes.
A 2-year-old boy's mother is concerned about his tendency to bite himself to
the point of bleeding. The boy's ringers show scarring and several scabs, and
his lips are swollen and bruised. He exhibits poor coordination, poor muscle
tone, and frequent jerking movements of his arms and legs. He is significantly
delayed in speech. His urine is orange in color and "gritty.“

5. Which of the following is the most likely diagnosis?.

A. Tay-Sachs disease
B. Gout
C. Lesch-Nyhan syndrome
D. Severe combined immunodeficiency ?
E. Cerebral palsy.
5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,
and de-velopmental delay are all consistent with a diagnosis of Lesch-Nyhan
syndrome. This disorder is due to deficiency of HGPRT, which prevents salvage of
hypoxanthine and guanine to their respective nucleotides, IMP and GMP. This
leads in turn to hyperactivlty of the purine synthesis pathway, excessive purine
degradation, and overproduc-tion of uric acid. The gritty substance and orange
color of the patient's urine are due to excretion of both dissolved uric acid and
precipitated sodium urate. Gout might account for the excessive uric acid
production but not the neurologic symptoms. Self-mutilation is not characteristic of
either Tay-Sach’s disease or cerebral palsy.
21.2 The catabolism of hemoglobin:

A. occurs in red blood cells.

B. involves the oxidative cleavage of the porphyrin ring.
C. results in the liberation of carbon dioxide.
D. results in the formation of protoporphyrinogen.
E. is the sole source of bilirubin.

Correct answer = B. The cyclic heme molecule is oxidatively

cleaved to form biliverdin. The catabolism occurs in the cells of
the reticulo-endothelial system, particularly the spleen, and results
in the liberation of carbon monoxide. Protoporphyrinogen is an
intermediate in the synthesis, not degradation, of heme.
Hemoglobin and tissue cytochromes are precursors of bilirubin.

?
CLINICAL PROBLEMS 135

A 44-year-old woman is brought to the emergency department doubled over

with abdominal pain. Her husband states that the pain began several hours
earlier, comes in waves, but has not really subsided completely even for brief
periods since then. Oral antacids have not helped the pain at all. Her
discomfort is not relieved by defecation. A stool sample is light gray or clay-
colored. Physical examination shows right upper quadrant abdominal pain.
Her sclerae are slightly yellow in color. A sonogram shows a 2-cm mass in
the region of the bile duct.

Testing of her serum would be expected to reveal elevated levels of which of

the following?.

A. Albumin-bound bilirubin.
B. Porphobilinogen.
C. Free, unconjugated bilirubin.
D. Conjugated bilirubin / Bilirubin Diglucuronide / Direct Bilirubin.
E. Biliverdin.

Ans: D. ?
148

CLINICAL PROBLEMS

1. Severe combined immunodeficiency arises from inhibition of

lymphocyte proliferation because B and T cells are particularly
sensitive to allosteric inhibition of which of the following enzymes
of purine nucleotide metabolism?.

A. Xanthine oxidase.
B. Dihydrofolate reductase.
C. Adenosine deaminase.
D. Ribonucleotide reductase.
E. Hypoxanthine-guanine phosphoribosyltransferase.

Ans: C.

?
5. A 2-year-old boy's mother is concerned about his tendency to bite himself to
the point of bleeding. The boy's fingers show scarring and several scabs, and
his lips are swollen and bruised. He exhibits poor coordination, poor muscle
tone, and frequent jerking movements of his arms and legs. He is significantly
delayed in speech. His urine is orange in color and "gritty.“

5. Which of the following is the most likely diagnosis?.

A. Tay-Sachs disease.
B. Gout.
C. Lesch-Nyhan syndrome.
D. Severe combined immunodeficiency. ?
E. Cerebral palsy.
5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,
and de-velopmental delay are all consistent with a diagnosis of Lesch-Nyhan
syndrome. This disorder is due to deficiency of HGPRT, which prevents salvage
of hypoxanthine and guanine to their respective nucleorides, IMP and GMP. This
leads in turn to hyperac-tivity of the purine synthesis pathway, excessive purine
degradation, and overproduction of uric acid. The gritty substance and orange
color of the patient's urine are due to excretion of both dissolved uric acid and
precipitated sodium urate. Gout might account for the excessive uric acid
production but not the neurologic symptoms. Self-mutilation is not characteristic
of either
CLINICAL PROBLEMS 148

4. Methotrexare is a potent anticancer agent that starves dividing

cells of deoxyribonucleotides through direct inhibition of which of
the following enzymes?.

A. Ribonucleotide reductase
B. Xanthine oxidase
C. Carbamoyl phosphate synthetase II
D. Thymidylate synthetase.

Ans: D.

?
CLINICAL PROBLEMS 135

A 44-year-old woman is brought to the emergency department doubled over

with abdominal pain. Her husband states that the pain began several hours
earlier, comes in waves, but has not really subsided completely even for brief
periods since then. Oral antacids have not helped the pain at all. Her
discomfort is not relieved by defecation. A stool sample is light gray or clay-
colored. Physical examination shows right upper quadrant abdominal pain.
Her sclerae are slightly yellow in color. A sonogram shows a 2-cm mass in
the region of the bile duct.

Testing of her serum would be expected to reveal elevated levels of which of

the following?.

A. Albumin-bound bilirubin.
B. Porphobilinogen.
C. Free, unconjugated bilirubin.
D. Conjugated bilirubin.
E. Biliverdin.

Ans: D. ?
148

CLINICAL PROBLEMS

1. Severe combined immunodeficiency arises from inhibition of

lymphocyte proliferation because B and T cells are particularly
sensitive to allosteric inhibition of which of the following enzymes
of purine nucleotide metabolism?.

A. Xanthine oxidase.
B. Dihydrofolate reductase.
C. Adenosine deaminase.
D. Ribonucleotide reductase.
E. Hypoxanthine-guanine phosphoribosyltransferase.

Ans: C.

?
CLINICAL PROBLEMS 148

4. Methotrexare is a potent anticancer agent that starves dividing

cells of deoxyribonucleotides through direct inhibition of which of
the following enzymes?.

A. Ribonucleotide reductase
B. Xanthine oxidase
C. Carbamoyl phosphate synthetase II
D. Thymidylate synthetase.

Ans: D.

?
5. A 2-year-old boy's mother is concerned about his tendency to bite himself to
the point of bleeding. The boy's fingers show scarring and several scabs, and
his lips are swollen and bruised. He exhibits poor coordination, poor muscle
tone, and frequent jerking movements of his arms and legs. He is significantly
delayed in speech. His urine is orange in color and "gritty.“

5. Which of the following is the most likely diagnosis?.

A. Tay-Sachs disease.
B. Gout.
C. Lesch-Nyhan syndrome. ?
D. Severe combined immunodeficiency.
E. Cerebral palsy.
5. The answer is C. This patient's self-mutilation behavior, neurologic symptoms,
and de-velopmental delay are all consistent with a diagnosis of Lesch-Nyhan
syndrome. This disorder is due to deficiency of HGPRT, which prevents salvage
of hypoxanthine and guanine to their respective nucleorides, IMP and GMP. This
leads in turn to hyperac-tivity of the purine synthesis pathway, excessive purine
degradation, and overproduction of uric acid. The gritty substance and orange
color of the patient's urine are due to excretion of both dissolved uric acid and
precipitated sodium urate. Gout might account for the excessive uric acid
production but not the neurologic symptoms. Self-mutilation is not characteristic
of either
For which of the following reactions S-adenosyl methionine
(SAM), serve as a methylating agent?.

A. Conversion of dopamine to norepinephrine.

B. Synthesis of creatine from ceratine P.
C. Synthesis of phosphatidylcholine from phosphatidylethanolamine.
D. Conversion of dUMP to dTMP.
E. Formation of methionine fro homosycteine.

Answer: C. The The conversion of dopamine to norepinephrine

Involved in the hydroxylation reaction. (SAM methylates
norepinephrine to form epinephrine). The synthesis of creatine
requires SAM, not The conversion conversion of creatine
phosphate to creatine.
?
X
Pregnant women frequently suffer from folate deficiencies.
A deficiency of folate would decrease the production of ,

A. Creatine phosphate from creatine.

B. All of the pyrimidines required for RNA synthesis.
C. The thymine nucleotide required for DNA synthesis.
D. Phosphatidylcholimne from diacylglycerol and CDP-choline.

Answer: C. The only pyrimidine that requires folate for its

synthesis is thymine (dUMP → dTMP). Folate is required for
incorporation of carbons 2 and 8 into all purine molecules. The
Synthesis of creatine phosphate and of phosphatidylcholine do not
Require folate. Folate deficiencies during pregnancy can lead to
Neural tube defects (e.g., spina bifida) in the fetus.
Excessive degradation of AMP and GMP would result in
Increased urinary excretion of,

A. Creatine
B. Urea
C. Uric Acid
D. Thiamine
E. Thymine

Answer: C. The purine bases, adenine (A) and guaninie (G), are
oxidized to uric acid, which is excreted in the urine. Excessive
Production of uric acid can result in the condition known as gout.

?
 he component that would be elevated to the greatest extent
n the blood of a person suffering from Gout is_______.
. bilirubin.
. uric acid.
. creatine kinase.
. blood urea nitrogen.
nswer: B.

?
he genetic defect in the hypoxanthine guanine
hosphoribosyl transferse (HGPRT) will leads to,
. Parkinson’s disease.
. Cystinuria.
. Pellagra.
. Lesch-Nyhan syndrome.
. Hartnup’s disease.

nswer: D. The defect in the purine salvage enzyme HGPRT

auses Lesch-Nyhan syndrome.

?
De novo pyrimidine synthesis requires,

A. Phosphorobosyl pyrophosphate (PRPP) for the initial step.

B. Tetrahydrofolate for the incorporation of carbon 2 and 8.
C. Both carbon and nitrogen of aspartate to form the ring.
D. NH4+ as a substrate for carbamoyl phosphate synthetase II.
E. Glycine as the source of two nitrogens in the ring.

Answer: C. Options A and B are true for purine synthesis. During

pyrimidine synthesis, the entire aspartate molecule is incorporated
Into the ring. Glutamine is the substrate for carbamoyl phosphate
synthase II, the enzyme involved in pyrimidine biosynthesis. (NH4+
Ions is the substrate for the synthase I in the urea synthesis).
Glycine supplies one nitrogen for purine synthesis.
5-Fluorouracil (5-FU) is an effective chemotherapeutic agent
Because interferes with DNA synthesis by directly inhibiting
the reaction in which,

A. FH2 → FH4.
B. dUMP → TMP.
C. Glutamine+ PRPP → Phosphoribosylamine.
D. Methyl B12 → B12 .

Answer: B. Methotrexate inhibits reaction A. 5-FU inhibits

reaction B. The remaining reactions are not directly affected by
5-FU. Reaction C is the first step in purine biosynthesis, and
reaction D provides the methyl group for the biosynthesis of
methionine from homocysteine.

?
7. 5-Fluorouracil (5-FU) is an effective chemotherapeutic agent
because it interferes with DNA synthesis by directly inhibiting
which of the following reactions?.
(A). Dihydrofolate (FH2) → tetrahydrofolate (FH4).

(B). Deoxyuridine monophosphate (dUMP) → ?

thymidinemonophosphate (dTMP).

(C). Glutamine + phosphoribosyl 1-pyrophosphate (PRPP) →

phosphoribosylamine.
(D). Methyl B12 → vitamin B12 .
(E). Vitamin B12 → methyl B12 .

Ans: B. Methotrexate inhibits the reaction of dihydrofolate (FH2) →

tetrahydrofolate (FH4), which is mediated by dihydrofolate reductase. 5-FU
inhibits the reaction of deoxyuridine monophosphate (dUMP)→ thymidine
monophosphate (dTMP). The remaining reactions are not directly affected by
5-FU. Glutamine to create phosphoribosylamine is the first step in purine
biosynthesis. Methyl B12 → vitamin B12 provides the methyl group for the
23. A 57-year-old sales representative for a biotechnology firm has a history of alcohol
abuse and hyperuricemia, He attends an out-of-town conference and gorges himself on
appetizers, including liver pate, caviar, aid sweetbreads before dinner. Early the
following morning he develops a painful swelling in his big toe. In addition to the alcohol
consumed with his meals, which of the component may have contributed to this
episode?.
A). Carbohydrate
B). Cholesterol
C). Nucleic acid
D). Protein ?
E). Triglyceride.
Answer is C. Purines from ingested nucleic acids are converted to uric acid by
intestinal epithelial cells and released into the blood for potential excretion by the
kidney. Foods rich in DNA (caviar) or RNA (liver pate and sweetbreads [pancreas],
derived from organs with active protein synthesis) are particularly rich sources of
purines, and their ingestion coupled with excess alcohol consumption presumably
increased his plasma urate levels to the point at which uric acid crystallized in a
susceptible joint. The resultant painful swelling is gout. The pain is caused by
precipitation of uric acid crystals in the joints with attendant inflammation.
Carbohydrate (choice A), cholesterol (choice B), protein (choice D), and TGs (choice
E) by themselves do not contain purines, and their metabolism does not contribute to
the uric acid pool. To the extent that protein-rich foods are cellular, they will, however,
contain nucleic acids that will be catabolized to uric acid.
18. Pregnant women frequently suffer from folate
deficiencies. A deficiency of folate would decrease the
production of

A. creatine phosphate from creatine.

B. all of the pyrimidines required for RNA synthesis.
C. the thymine nucleotide required for DNA synthesis.
D. phosphatidylcholine from diacylglycerol and CDP-choline.

18-C. The only pyrimidine that requires folate for its synthesis is
thymine (dUMP → dTMP). Folate is required for incorporation of
carbons 2 and 8 into all purine molecules. The synthesis of
creatine phosphate and of phosphatidylcholine do not require
folate. Folate deficiencies during pregnancy can lead to neural
tube defects (e.g., spina bifida) in the fetus.

?
25. Excessive degradation of AMP and GMP would result in
Increased urinary excretion of

A. Creatinine.
B. Urea.
C. Uric acid.
D. Thiamine.
E Thymine.

25-C. The purine bases, adenine (A) and guanine (G), are
oxidized to uric acid, which is excreted in the urine. Excessive
production of uric acid can result in the condition known as gout.

?
26. De novo pyrimidine synthesis requires

A. phosphoribosyl pyrophosphate (PRPP) for the initial step.

B. tetrahydrofolate for the incorporation of carbons 2 and 8.
C. both carbon and nitrogen of aspartate to form the ring.
D. NH4+ as a substrate for carbamoyl phosphatesynthetase II.
E. glycine as the source of two nitrogens in the ring.

26-C. Options A and B are true for purine but not pyrimidine
biosynthesis. During pyrimidine synthesis, the entire aspartate
molecule is incorporated into the ring. Glutamine is the substrate
for carbamoyl phosphate synthetase II, the enzyme involved in
pyrimidine biosynthesis. (NH4+ is the substrate for synthetase I
used in urea synthesis.) Glycine supplies one nitrogen for purine
synthesis.

?
27. 5-Fluorouracil (5-FU) is an effective chemo-therapeutic
agent because it interferes with DNA synthesis by directly
inhibiting the reaction in which

A. FH2 → FH4.
B. dUMP → dTMP
C. glutamine + PRPP → phosphoribosylamine
D. methyl B12 → B12 .

27-B. Methotrexate inhibits reaction A. 5-FU inhibits reaction B.

The remaining reactions are not directly affected by 5-FU.
Reaction C is the first step in purine biosynthesis, and reaction D
provides the methyl group for the biosynthesis of methionine
from homocysteine.

?
59. Match each condition below with the component that would be
elevated to the greatest extent in the blood.
Disease Answer Component
A. Gout 1. Bilirubin

B. Myocardial infarction 2. Uric acid

C. Hepatitis 3. Creatine kinase
D. Kidney disease. 4. Blood urea nitrogen
(BUN)

A-2 Uric acid

B-3 Creatine kinase
C-1 Bilirubin ?
D-4 BUN.
In gout, uric acid crystals precipitate in joints, causing severe pain.
 Match each Disorder below with the Enzyme
Deficiency

Disorder Answer Enzyme Deficiency

1.Congenital Erythropoietic Uroporphyrinogen

Porphyria Decarboxylase.
2. Porphyria Cutanea B. Uroporphyrinogen III
Tarda (PCT) Synthase.
3. Erythropoietic Ferrochelatase.
Proptoporphyria

Ans: 1-B, 2-A, 3-C.

?
11. A 56-year-old diabetic with end-stage renal disease receives a
kidney transplant from his son. His nephrologist is concerned for
the possibility of transplant rejection and puts the patient on
mycophenolic acid, which inhibits which important enzyme in the
synthesis of nucleotides?.

A. PRPP.
B. IMP dehydrogenase
C. Adenylosuccinate synthase.
D. Ribonucleotide reductase. ?
E. Adenylosuccinase.

Answer-B. Mycophenolic acid, a potent immunosuppressant, is an

inhibitor of IMP dehydrogenase, which normally converts IMP to
xanthosine monophosphate. PRPP synthase catalyses the initial step in
nucleotide metabolism, forming PRPP from ATP and ribose.
Adenylosuccinate synthase and adenylosuccinase are sequential
enzymes in the synthesis of AMP.
15. A child is noted to have recurrent respiratory infections that necessitate
hospitalization. His lab tests demonstrate a decrease in T cells, B cells, and
natural killer cells and decreased antibodies. He is found to have severe
combined immuno-deficiency (SCID). The enzyme that is defective in this
disorder is important in which of the following processes?.
A. Conversion of ribonucleotides to deoxyribonucleotides.
B. Formation of AMP. ?
C. Degradation of deoxyadenosine triphosphate (dATP)
D. Synthesis of UMP.
E. Conversion of deoxyuridine mono-phosphate (dUMP) to
thymidinemonophosphate (dTMP).

Answer-C. The enzyme deficiency in severe combined immunodeficiency

(SCID) is likely adenosine deaminase, which normally degrades adenosine to
inosine. The conversion of ribonucleotides to deoxyribonucleotides is
performed by ribonucleotide reductase. AMP is formed from IMP through the
action of adenylosuccinate synthetase, followed by the action of
adenylosuccinate. UMP synthase is an important enzyme in the formation of
UMP and, subsequently, cytidine triphosphate (CTP) and thymidine
triphosphate (TTP). The conversion of deoxyuridine monophosphate
(dUMP) to thymidine mono-phosphate (dTMP) is mediated by thymidylate
17. A 58-year-old man is awoken by a throbbing ache in his
great toe. He has suffered these symptoms before, usually after
indulging in a rich meal. On exam, he is noted to have an angry
inflamed great toe; also of note are several small nodules on the
antihelix of his ear. Inhibition of which of the following enzymes
might prevent further occurrences of this man's ailments?.
A. Carbamoyl phosphate synthetase-II.
B. Hypoxanthine-guanine phosphoribosyl transferase (HGPRT).
C. PRPP synthetase.
D. Xanthine oxidase.
?
E. Orotate phosphoribosyl transferase.
Answer-D. Gout is caused by either the increased production or reduced
excretion of uric acid, leading to the deposition of urate crystals. Allopurinol, a
xanthine oxidase inhibitor, decreases the production of urate from
hypoxanthine and xanthine. Carbamoyl phosphate synthase-II is an enzyme in
pyrimidine biosynthesis. HGPRT is an enzyme in the pathway for purine
salvage. Orotate phosphoribosyi transferase is important in the synthesis of
pyrimidines. PRPP synthetase is an important enzyme in the biosynthesis of
purines; overactivity can cause gout.
6. A 36-year-old Greek man with viral pneumonia has a self-
limiting episode of hemolysis. Over the next week, he has an
increased rate of reticulocytosis. Which of the following
compounds serves as a precursor to heme in the reticulocytes?.

A. α-Ketoglutarate
B. Fumarate
C. Isocitrate
D. Oxaloacetate
E. Succinyl-CoA

Ans: E.

?
8. A 23-year-old, single, unemployed woman in her eighth month
of pregnancy is seen in a volunteer-staffed obstetrics clinic. Her
first child, born at home and exclusively breast-fed, had
prolonged diarrhea and died from an intracranial hemorrhage at 1
month of age. To help prevent a similar problem in this
pregnancy, the resident gives her a free prescription for a vitamin
and advises her to take one 20-mg tablet each day. He also
informs her that the infant should receive an injection of this
vitamin soon after birth. The vitamin prescribed is required as a
coenzyme by which of the following enzymes?.

(A). δ-Aminolevulinate synthase

(B). ‫ﻻ‬-GlutamyI carboxylase
(C). Homocysteine methyltransferase
(D). Prolyl hydroxylase
(E). Thrombin.

Ans: A. ?
13. A 9-year-old girl with mild mental retardation was healthy at
birth but presented during the first week of life with vomiting,
lethargy, seizures, and hypertonia. An amino acid screen
revealed elevated levels of leucine, isoleucine, and valine, so
the child was put on a special diet restricted in these amino
acids. She has had no medical problems related to her disease
since that time. Which of the following enzymes is most likely
deficient in this child?.

A. Branched chain ketoacid dehydrogenase

B. Cystathionine synthase
C. Methylmalonyl CoA mutase
D. Ornithine transcarbamoylase
E. Propionyl CoA carboxylase.

Ans: A.

?
The Reactions of the Urea Cycle

NAG
De novo Pyrimidine Synthesis
 Alkaptonuria
 Deficiency of
homogentisate
dioxygenase.
 Urine turns dark on
standing.

 Oxidation of
homogentisic acid.

 Asymptomatic in
childhood.

 Tendency toward
arthritis in adulthood.
PKU, Tyrosemia & Alkaptonuria
Pathway of Porphyrin Synthesis:
Formation of Porphobilinogen

PLP

PLP = Pyridoxal phosphate

. A 48-year-old man developed abdominal colic, muscle pain,
nd fatigue. Following a 3-week hospitalization, acute intermittent
orphyria was initially diagnosed based on a high level of urinary
-aminolevulinic acid. Subsequent analysis of the patient’s
rculating RBCs revealed that 70% contained elevated levels of
nc protoporphyrin, and the diagnosis was corrected. The correct
iagnosis is most likely to be, .

. Protoporphyria.
. Congenital erythropoietic porphyria.
. Lead poisoning.
. Barbiturate addiction .
. Iron deficiency.

nswer: C. Lead inhibits both ferrocheatase (increasing the zinc

rotoporphyrin) and ALA dehydrase (increasing δ -ALA)
PLP
De novo Pyrimidine Synthesis
 Synthesis of Purine Nucleotides, Showing the
Inhibitory Effect of Some Structural Analogs

 PRPP is an allosteric
Positive modulator in
the step 1.

 AMP, CMP & IMP are

Inhibitors in step 1.
The Reactions of the Urea Cycle

NAG
 Intermediary Metabolism Related to
Nitrogen Metabolism & The Urea Cycle
CO2-
+
H3N-C-H
CH2
CH2 Mitochondrion
CO2-

Glu Urea
Cycle

Cytosol

TCA Cycle
The Reactions
Mitochondria
of the Urea
Cycle
*
NAG:N-acetyl Cytosol
glutamate; (in the
formation of urea, *
one amino group is
derived from free
NH4+ ion, while the
other is from NAG
aspartate. Carbon is *
obtained from CO2.
(*) mitochondrial
enzymes, the rest of
the enzymes are
 The Ornithine Aminotransferase Reaction

Ornithine aminotransferase

This is a reversible reaction dependent on PLP, which

normally favors ornithine degradation.
Synthesis of Glutamine & its Conversion to Glutamate

*
The reactions are independent and irreversible
The Reactions
Mitochondria
of the Urea
Cycle
*
NAG:N-acetyl Cytosol
glutamate; (in the
formation of urea, *
one amino group is
derived from free
NH4+ ion, while the
other is from * NAG
aspartate. Carbon is *
obtained from CO2.
(*) mitochondrial
enzymes, the rest of
the enzymes are
 Biosynthesis of Catecholamines
PLP

Catecholamins: include adrenaline, noradrenaline and

dopamine (DOPA), with roles as hormones and
neurotransmitters. Catecholamines (epinephrine and
norepinephrine) are produced naturally in the body and function
as key neurologic chemicals.
Synthesis of dTMP from dUMP, Ilustrating
Sites of Action of Antineoplastic Drugs

5-Fluorouracil: An antineoplastic agent, used

especially in the treatment of cancers of the skin,
breast, and digestive system.

Methotrexate: An anticancer drug that acts as a

folic acid antagonist to interfere with cellular
reproduction and is used in the treatment of
psoriasis, certain cancers, and certain inflammatory
diseases, such as rheumatoid arthritis.
 Salvage Pathways of Purine
Nucleotide Synthesis

Lesch-Nyhan Syndrome is characterized

by the deficiency of hypoxanthine-guanine
phosphoribosyl transferase (HGPRT), leads
to accumulation of PRPP and uric acid, the
condition is know as “Hyperuricemia”.
Hyperuricemia is the presence of high levels of uric
acid / sodium urate crystals in the blood. The upper
end of the normal range is 360 µmol/L (6 mg/dL) for
women and 400 µmol/L (6.8 mg/dL) for men.

PRPP=Phosphoribosyl pyrophospate.
Phenylketoneuria (PKU)

Deficiency
Enzyme Deficiency in Homocystinuria
Trans-Sulfuration Pathway
Trans-Sulfuration pathway is
analagous to transamination for AAs.

Two RXNs, both use pyridoxal

phosphate (Vit B6) as a cofactor (as
with transamination).

☻
Cystathionuria
Cystathinase

B6
Homocystinuria PLP NH3
Summary of the
Metabolism of
Amino Acids
 Biosynthesis of Catecholamines
PLP
*
*
*

Catecholamins: include adrenaline, noradrenaline & dopamine

(DOPA), with roles as hormones and neurotransmitters.

Catecholamines (epinephrine & norepinephrine) are produced

naturally in the body and function as key neurologic chemicals.
Ubiquitin-Proteosome Degradation
Pathway of Proteins
Key Concept Map For Heme Metabolism

*
Synthesis of dTMP from dUMP, Ilustrating
Sites of Action of Antineoplastic Drugs

5-Fluorouracil: An antineoplastic agent, used

especially in the treatment of cancers of the skin,
breast, and digestive system.

Methotrexate: An anticancer drug that acts as a

folic acid antagonist to interfere with cellular
reproduction and is used in the treatment of
psoriasis, certain cancers, and certain inflammatory
diseases, such as rheumatoid arthritis.
 What determines whether a
protein will become ubiquinated?
Half-Life of the Amino Acids
Excretion of Nitogenous Waste Products
The carbon chains are
Amino acids broken down to molecules
Most mammals convert that feed into the TCA
amino-acid nitrogen to cycle.
urea for excretion NH4+
Some animals
excrete NH4+ or
uric acid.

Most terrestrial
vertebrates Fish & other Birds & reptiles
aquatic vertebrates

O
H
O HN N
NH4+ * O
H2N-C-NH2
Ammonium ion Uric acid N N
Urea O H
H
Degradation of
Purine
Nucleotides to
Uric Acid

*
Enzyme Deficiency in Homocystinuria
Trans-Sulfuration Pathway
Trans-Sulfuration pathway is
analagous to transamination for AAs.

Two RXNs, both use pyridoxal

phosphate (Vit B6) as a cofactor (as
with transamination).

☻
Cystathionuria
Cystathinase

B6
Homocystinuria PLP NH3
*

Albinism
Patient with oculocutaneous
albinism, showing blond hair &
white eyebrows and lashes.
Transport of Ammonia from
Peripheral Tissues to the Liver
Genetic Deficiencies in Some of the Urea Cycle
Enzymes can be Treated Pharmacologically
CO2-
Benzoate CO2- Phenylacetate

ATP + CoA-SH ATP + CoA-SH

AMP + PPi AMP + PPi

O
S-CoA
Benzoyl-CoA S-CoA
O Phenylacetyl-CoA
Glycine Glutamine

CoA-SH O CoA-SH
H
N CO2-
N CO2 -
Phenylacetyl-
Hippurate H
O glutamine
(benzoylglycine)
O

NH2

The amide products of these reactions (hippurate and phenylacetylglutamine)

are excreted in the urine. Synthesizing the Gly or Gln removes ammonia.
Lesions of the Lips of Lesch-Nyhan Patient
Caused by Self-mutilation
De novo Synthesis Precursors

Ribonucleotides!
Formation of Bilirubin From Heme
Dubin-Johnson syndrome is an autosomal
recessive disorder which causes an increase
of conjugated bilirubin without elevation of liver
ALT & AST.

Defect in the ability of hepatocytes to secrete

conjugated bilirubin into the bile. It is usually
asymptomatic but may be diagnosed in early
infancy based on laboratory tests.
?
Enterohepatic circulation refers to the circulation of bile
from the liver, where it is produced, to the small intestine,
where it aids in digestion of fats and other substances,
back to the liver. Endogenous bacteria play an important
role in enterohepatic circulation.
 ENDOCYTOSIS
Exocytosis:Macromolecules and particles enter the cell by endocytosis.
Phagocytosis- part of the plasma membrane engulf large particles
a. Phagosome + lysome = Phagolysosome.

Exocytosis
Cytoplasm
 ENDOCYTOSIS
Endocytosis:Macromolecules and particles enter the cell by endocytosis.
Phagocytosis- part of the plasma membrane engulf large particles
a. Phagosome + lysome = Phagolysosome.

Phagocytosis (Cellular Eating).

The Glucose-Alanine Cycle
When muscles produce Alanine Liver
lactate during times of Nitrogen
decreased O2, they also
Carbon
produce alanine. This
alanine is shuttled to the Urea
liver where it is used to
make glucose. Glucose
Urine
Muscle

Alanine
Amino α-KG
acid 1
Glutamate Pyruvate
α-
Keto Glycolysis
acid1 Glucose
 Reactions Catalyzed During AA Catabolism

Alanine Aminotransferase &

Aspartate Aminotransferase
estimations are widely used to
assess liver function.

A. Alanine Aminoransferase
B. Aspartate Aminotransferease
A patient presents with Hemolytic Anemia. Which of the following
should be elevated in the BLOOD?.

A. Bilirubin
B. Ammonia
C. Urea
D. Mitochondria
E. Ribose

Ans: A.
Your patient is a 60-year-old male who has a long history of
alcohol abuse. He is confused, has an enlarged liver, and a
flapping tremor at the wrist (asterixis). Your diagnosis is hepatic
encephalopathy. A treatment is a diet of branched-chain amino
acids. Which one of the following sets of amino acids is
composed of branched-chain amino acids?.

A. Methionine, proline, and cysteine.

B. Glycine, alanine, and serine.
C. Valine, leucine, isoleucine.
D. Aspartate, glutamate, and asparagine.
E. Tryptophan, phenylalanine, and tyrosine.

Ans: C. Only valine, leucine, and isoleucine compose the only

set of branched-chain amino acids.
The Glucose-Alanine Cycle
When muscles produce Alanine Liver
lactate during times of Nitrogen
decreased O2, they also
Carbon
produce alanine. This
alanine is shuttled to the Urea
liver where it is used to
make glucose. Glucose
Urine
Muscle

Alanine
Amino α-KG
acid 1
Glutamate Pyruvate
α-
Keto Glycolysis
acid1 Glucose
1.Which biomolecule acts as a positive modulator for the first step
of the urea cycle which is catalyzed by carbamoyl phosphate
synthetase-I (CPS-I).

A. Gultamate.
B. Glutamine.
C. N-Acetyl Glutamate (NAG).
D. Aspartate.
E. Ammonium ions (NH4+).

Ans: C.
7. Which of the following is a common compound shared by The
TCA cycle and the urea cycle?

A. α-ketoglutarate.
B. Succcinyl Coenzyme A (CoA).
C. Oxaloacetate.
D. Fumarate.*
E. Arginine.

Ans: D.
8. Which of the following enzymes requires adenosine
triphosphate (ATP) to mediate its reactions?

A. Argininosuccinate lyase.
B. Argininosuccinate synthetase.
C. Arginase.
D. Glutaminase.
E. Ornitine transcarbamoylase.

Ans: B.
10. Two days after a full-term normal delivery, a neonate begins
to hyperventilate, develops hypothermia and cerebral edema,
and becomes comatose. Urinalysis reveals high levels of
glutamine and orotic acid. The BUN is below normal. Which
enzyme is most likely to be deficient in this child?

A. Cytoplasmic glutaminase.
B. Cytoplasmic carbamoyl phosphate synthetase.
C. Cytoplasmic orotidylate decarboxylase.
D. Mitochondrial carbamoyl phosphate synthetase.
E. Mitochondrial ornitihine transcarbamoylase.

Ans: E.
11. Transamination reactions are essential for ammonia
assimilation. What cofactor is required to catalyze
transamination reactions?

A. pyridoxal phosphate (PLP).

B. thiamin pyrophosphate.
C. biotin.
D. NAD+.
E. NADPH.

Ans: A.
12. Which of the following enzymes function in the biological
assimilation of ammonia?

A. Glutamate dehydrogenase.
B. Glutamine synthetase.
C. Glutamate synthase.
D. All of the above.***
E. None of the above.

Ans: D.
A 55-year-old man suffers from cirrhosis of the liver. Toxins such
as ammonia are not properly metabolized by the liver and can
now damage structures such as the brain. Which of the following
amino acids covalently binds ammonia and transports and stores
it in a nontoxic form?

A. Aspartate.
B. Glutamate.
C. Serine.
D. Cysteine.
E. Histidine.

Ans: B.
14. Which amino acid participates as a pathway intermediate in
the urea cycle?

A. Lysine.
B. Arginine.***
C. Glutamine.
D. Histidine.
E. Tyrosine.

Ans: B
Urea Cycle Must Know Key Points
1. Urea cycle occurs partly in ……….. and partly in the ……….

Ans: Mitochondria, Cytosol / Cytoplasm.

2. The rate-limiting step (committed step) in the urea cycle is

catalyzed by the enzyme …………

Ans: Carbamoyl phosphate synthetase-I (CPS-I).

3. The biomolecule acts as a positive modulator in the first step of

the urea cycle is……………
Ans: N-Acetyl glutamate (NAG).

4. ………….can be converted to arginine by a series of reactions,

some of which requires urea cycle enzymes.
Ans: Glutamate.
5. The enzymes are responsible for producing the direct donors of nitrogen into the
pathway producing urea, include ………. And ………..
Ans: Aspartate aminotransferase and carbmoyl phosphate sythetase.

6. The accumulation of glutamine and orotic acid in the bood and an ultimate ammonia
toxicity in the newborn is due to the deficiency of the urea cycle enzyme……….
Ans: Mitochondrial ornitihine transcarbamoylase (OTC).
7. The common nitrogen acceptor for all reactions involving transaminase is ……………

Ans: α-ketoglutarate.

8. The common nitrogen donor for all reactions involving transaminase is ……………

Ans: Oxaloacetate (OAA).

9. The common compound shared by the TCA cycle and the urea cycle is ………………
Ans: Fumarate.
10. Hyperammonemia caused by a congenital defect of the urea cycle
enzyme………..which is characterized by accumulation of excess amount of arginine
in the blood.

Ans: Arginase.
11. The urea cycle enzyme which requires adenosine triphosphate (ATP) to mediate its
reactions is ?.

Ans: Argininosuccinate synthetase.

12. The reaction catalyzed by an urea cycle enzyme ornithine aminotransferase which
requires --------- as a coenzyme, which converts ornithine and α-ketoglutarate into
glutamate.

Ans: Pyridoxal phosphate (PLP).

 Match the Urea Cycle Disorders With the
Enzyme Defect
No Disorder Answer Enzyme Defect

1 Hyperammonemia type I A. Argininosuccinate synthase

2 Hyperammonemia type II B. Ornithine transcarbomylase (OTC)

3 Citrullinemia C. Argininosuccinate lyase

4 Argininosuccinic Aciduria D. Arginase

5 Hyperargininemia E. Carbamoyl-P synthase-I (CPS)

Answer: 1E; 2-B; 3-A; 4-C; 5-D

Genetic Deficiencies in Some of the Urea Cycle Enzymes can be Treated
Pharmacologically by eliminating the amino acids such as glycine and glutamine by
administering,

A. Aspartic acid.
B. Benzoic acid and phenylacetate.
C. GABA.
D. Pyridoxal phosphate.
E. Methionine.

Ans: B. The amide products of these reactions (hippurate and

phenylacetylglutamine) are excreted in the urine. Synthesizing the Gly or Gln
removes ammonia.
The Reaction Catalyzed by Glutamate Dehydrogenase which reversibly converts
glutamate to α-ketoglutarate require the cofactor,

A. ATP
B. NAD
C. NAD(P)+ /NAD(P)H.
D. Biotin
E. Pyridoxal phosphate.

Ans: C. The cofactors require by the glutamate dehydrogenase is

NAD(P)+ /NAD(P)H.
Hyper ammonemia II is characterized by mitochondrial ornithine transcarbamoylase
deficiency, with the common signs and symptoms include hyperventilation, develops
hypothermia and cerebral edema, and becomes comatose. Patients urine will show
increased excretion of glutamine and orotic acid, but BUN will be below normal.

Glutamate: The amino acids glutamate covalently binds ammonia and transports and
stores it in a nontoxic form.
Arginase: The urea cycle enzyme arginase deficiency will lead to the accumulation of
NH4+ ions in blood, characterized by vomiting and tremors.

Aspartate: Via the enzymes of urea cycle, aspartate provides nitrogen for synthesis of
arginine, it provides NH2 group.
Ammonium ions (NH4+) and CO2 will accumulate in blood in the absence of a CPS-I,
Hyperammonemia due to CPS-I deficiency.
Via the enzymes of urea cycle, aspartate provides nitrogen for
synthesis of arginine, the guanidine group of arginine will be
releases as urea and the byproduct ornithine, ornithine will be
transferred to mitochondria.

LFTs: Estimation of serum ALT, AST, gamma glutamyl trasferase, alkaline

phosphatase, total protein, albumin/globulin ratio, bilirubin estimation will be helpful to
evaluate liver function, and hence referred as liver function tests (LFTs).

Urea synthesis will increase on high protein diet, prolonged starvation and muscle
wasting diseases.
The urea cycle enzyme Arininosuccinate synthetase requires adenosine
Triphosphate (ATP) to mediate its reaction

Fumarate is the common compound shared by Urea Cycle and TCA cycle.

The amino acid ornitine will be recycled between mitochondria and cytoplasm in
urea cycle.

The rate-limiting step in Urea cycle is catalyzed by CPS-I,

 Presence of excess amount of CO2 and NH4+ ions and aspartate and
availability of NAG stimulates the Urea cycle, and hence ammonia toxicity will be
cleared as urea production and excretion in urine. Sodium benazoate
administration will reduce ammonia toxicity by utilizing glycine and increasing the
excretion of glycine as Hippuric acid.