BIOKIMIA (II)

By Laida Neti Mulyani, M.Si

Kontrak Kuliah

TUGAS
Presensi (10%)
Rata rata tugas (90%)
UTS
UTS (65%)
Kuis (35%)
Overview
Metabolisme
 Overview Metabolisme
Metabolic pathways fall into three categories
Anabolic pathways
Those involved in the synthesis of compounds.

Catabolic pathways
Involved in the breakdown of larger molecules,
commonly involving oxidative reactions
Producing reducing equivalents and, mainly via the
respiratory chain, ATP.

Amphibolic pathways
Occur at the crossroads of metabolism, acting as
links between the anabolic and catabolic pathways, eg,
the citric acid cycle.
Outline of the pathways for the catabolism
of dietary carbohydrate, protein, and fat
Carbohydrate Metabolism

Glucose is metabolized to pyruvate by the pathway of

glycolysis, which can occur anaerobically (in the
absence of oxygen), when the end product is lactate.
Aerobic tissues metabolize pyruvate to acetyl-CoA,
which can enter the citric acid cycle for complete
oxidation to CO2 and H2O, linked to the formation of ATP
in the process of oxidative phosphorylation
Metabolisme glukosa
Overview of carbohydrate
metabolism
Lipid Metabolism Is Concerned Mainly
With Fatty Acids & Cholesterol

The source of long-chain fatty acids is either dietary

lipid or de novo synthesis from acetyl-CoA derived from
carbohydrate. Fatty acids may be oxidized to acetyl-
CoA (-oxidation) or esterified with glycerol, forming
triacylglycerol (fat) as the bodys main fuel reserve.
Fatty acid metabolism
 Amino Acid Metabolism

The amino acids are required for protein synthesis.

Some must be supplied in the diet (the essential amino
acids) since they cannot be synthesized in the body.
The remainder are nonessential amino acids that are
supplied in the diet but can be formed from metabolic
intermediates by transamination, using the amino
nitrogen from other amino acids.
After deamination, amino nitrogen is excreted as urea,
and the carbon skeletons that remain after transamination
(1) are oxidized to CO2 via the citric acid cycle
(2) form glucose (gluconeogenesis)
(3) form ketone bodies
Overview of amino acid metabolism
Transport and fate of major carbohydrate and amino
acid substrates and metabolites
Transport and fate of major lipid substrates and
metabolites
 The Citric Acid Cycle
The citric acid cycle (Krebs cycle, tricarboxylic acid
cycle) is a series of reactions in mitochondria that
oxidize acetyl residues (as acetyl-CoA) and reduce
coenzymes that upon reoxidation are linked to the
formation of ATP

The citric acid cycle is the final common pathway

for the aerobic oxidation of carbohydrate, lipid, and
protein because glucose, fatty acids, and most
amino acids are metabolized to acetyl-CoA or
intermediates of the cycle
Citric acid cycle, illustrating the catalytic
role of oxaloacetate.
 The citric acid cycle:
The major catabolic pathway for
acetyl-CoA in aerobic organisms.

Acetyl- CoA, the product of

carbohydrate, protein, and lipid
catabolism, is taken into the
cycle, together with H2O, and
oxidized to CO2 with the
release of reducing equivalents
(2H).
Subsequent oxidation of 2H in
the respiratory chain leads to
coupled phosphorylation of
ADP to ATP.
For one turn of the cycle, 11~P
are generated via oxidative
phosphorylation and 1~P arises
at substrate level from the
conversion of succinyl-CoA to
succinate.
The citric acid (Krebs) cycle
TWELVE ATP ARE FORMED PER TURN
OF THE CITRIC ACID CYCLE

As a result of oxidations catalyzed by the

dehydrogenases of the citric acid cycle, three molecules
of NADH and one of FADH2 are produced for each
molecule of acetyl-CoA catabolized in one turn of the
cycle.

These reducing equivalents are transferred to the

respiratory chain where reoxidation of each NADH
results in formation of 3 ATP and reoxidation of FADH2 in
formation of 2 ATP. In addition, 1 ATP (or GTP) is formed
by substrate-level phosphorylation catalyzed by
succinate thiokinase.
 Involvement of the citric acid cycle
in transamination and gluconeogenesis.
Participation of the citric acid cycle in
fatty acid synthesis from glucose
 Jumlah energi dari glikolisis dan
Daur Krebs
Glukosa
8 ATP

2 Piruvat
2x3= 6 ATP

2 Asetil koenzim-A
2x12 = 24 ATP
38 ATP
Daur Krebs

CO2 dan H2O

 Regulasi
siklus TCA
 The allosteric inhibition of pyruvate oxidation is
greatly enhanced when long-chain fatty acids are
available. AMP,CoA, and NAD, all of which
accumulate when too little acetate flows into the
citric acid cycle, allosterically activate the PDH
complex
Thus, this enzyme activity is turned off when
ample fuel is available in the form of fatty acids
and acetyl-CoA and when the cells [ATP]/[ADP]
and [NADH]/[NAD] ratios are high, and it is turned
on again when energy demands are high and the
cell requires greater flux of acetyl-CoA into the
citric acid cycle
Glikolisis dan Glukoneogenesis
ASPEK BIOMEDIK GLIKOLISIS

Diseases in which enzymes of glycolysis (eg, pyruvate

kinase) are deficient are mainly seen as hemolytic anemias
or, the defect affects skeletal muscle (eg, osphofructokinase),
as fatigue.
In fast-growing cancer cells, glycolysis proceeds at a higher
rate than is required by the citric acid cycle, forming large
amounts of pyruvate, which is reduced to lactate and
exported. This produces a relatively acidic local environment
in the tumor which may have implications for cancer therapy.
The lactate is used for gluconeogenesis in the liver, an
energy-expensive process responsible for much of the
hypermetabolism seen in cancer cachexia.
Lactic acidosis results from several causes, including
impaired activity of pyruvate dehydrogenase
Glikolisis
 Tahapan Glikolisis
1. Phosphorylation of Glucose
2. Conversion of Glucose 6-Phosphate to Fructose 6-
Phosphate
3. Phosphorylation of Fructose 6-Phosphate to Fructose 1,6-
Bisphosphate
4. Cleavage of Fructose 1,6-Bisphosphate
5. Interconversion of the Triose Phosphates
6. Oxidation of Glyceraldehyde 3-Phosphate to 1,3-
Bisphosphoglycerate
7. Phosphoryl Transfer from 1,3-Bisphosphoglycerate to ADP
8. Conversion of 3-Phosphoglycerate to 2-Phosphoglycerate
9. Dehydration of 2-Phosphoglycerate to
Phosphoenolpyruvate
10. Transfer of the Phosphoryl Group from
Phosphoenolpyruvate to ADP
 Enzim Hexokinase dihambat secara alosterik
oleh produknya, yaitu G6-P. Dalam jaringan
dibandingkan di hati dan sel B pankreas
ketersediaan glukosa ( atau glikogen sintesis
pada otot dan lipogensis pada jaringan adiposa)
dikontrol melalui transpor di dalam sel, yang
diregulasi kebali oleh insulin.
Oksidasi glukosa dibawahOxidation of Glucose
Yields Up to 38 Mol of ATP Under Aer kondisi
aerob akan menghasilkan 38 mol ATP tapi hanya
2 mol ketika tidak terdapat O2
Piruvat dehidrogenase di regulasi oleh inhibisi
product akhir dan modifikasi kovalen
 Clinical Aspect
Arsenite and mercuric ions react with the SH
groups of lipoic acid and inhibit pyruvate
dehydrogenase, as does a dietary deficiency of
thiamin, allowing pyruvate to accumulate.
Nutritionally deprived alcoholics are thiamin-
deficient and may develop potentially fatal pyruvic
and lactic acidosis
Patients with inherited pyruvate dehydrogenase
deficiency, which can be due to defects in one or
more of the components of the enzyme complex,
also present with lactic acidosis, particularly after
a glucose load. Because of its dependence on
glucose as a fuel, brain is a prominent tissue where
these metabolic defects manifest themselves in
neurologic disturbances.
 Clinical Aspect

Inherited aldolase A deficiency and pyruvate

kinase deficiency in erythrocytes cause
hemolytic anemia. The exercise capacity of
patients with muscle phosphofructokinase
deficiency is low, particularly on high-
carbohydrate diets. By providing an alternative
lipid fuel, eg, during starvation, when blood free
fatty acids and ketone bodies are increased, work
capacity is improved.
 Clinical Aspect

Glucose uptake and glycolysis proceed about ten times

faster in most solid tumors than in noncancerous tissues.
Tumor cells commonly experience hypoxia (limited oxygen
supply), because they initially lack an extensive capillary
network to supply the tumor with oxygen. As a result, cancer
cells more than 100 to 200 m from the nearest capillaries
depend on anaerobic glycolysis for much of their ATP
production. They take up more glucose than normal cells,
converting it to pyruvate and then to lactate as they recycle
NADH. The high glycolytic rate may also result in part from
smaller numbers of mitochondria in tumor cells; les ATP
made by respiration-linked phosphorylation in mitochondria
means more ATP is needed from glycolysis.
 Clinical Aspect

In addition, some tumor cells overproduce several

glycolytic enzymes, including an isozyme of hexokinase
that associates with the cytosolic face of the mitochondrial
inner membrane and is insensitive to feedback inhibition
by glucose 6-phosphate. This enzyme may monopolize
the ATP produced in mitochondria, using it to convert
glucose to glucose 6-phosphate and committing the cell to
continued glycolysis. The hypoxia-inducible transcription
factor (HIF-1) is a protein that acts at the level of mRNA
synthesis to stimulate the synthesis of at least eight of the
glycolytic enzymes. This gives the tumor cell the capacity
to survive anaerobic conditions until the supply of blood
vessels has caught up with tumor growth.
Clinical Aspect
Fatty acid Catabolisme
Cells can obtain fatty acid fuels from three sources:
Fats consumed in the diet,
Fats stored in cells as lipid droplets,
Fats synthesized in one organ for export to another.

On average, 40% or more of the daily energy requirement

of humans in highly industrialized countries is supplied by
dietary triacylglycerols (although most nutritional guidelines
recommend no more than 30% of daily caloric intake from
fats)
Triacylglycerols provide more than half the energy
requirements of some organs, particularly the liver, heart,
and resting skeletal muscle. Stored triacylglycerols are
virtually the sole source of energy in hibernating animals
and migrating birds. Protists obtain fats by consuming
organisms lower in the food chain, and some also store
fats as cytosolic lipid droplets. Vascular plants mobilize
fats stored in seeds during germination, but do not
otherwise depend on fats for energy.
 Genetic Defects in Fatty AcylCoA
Dehydrogenases Cause Serious Disease

Stored triacylglycerols are typically the chief source of

energy for muscle contraction, and an inability to oxidize
fatty acids from triacylglycerols has serious consequences
for health. The most common genetic defect in fatty acid
catabolism in U.S. and northern European populations is
due to a mutation in the gene encoding the medium-
chain acyl-CoA dehydrogenase (MCAD).
The disease is characterized by recurring episodes of a
syndrome that includes fat accumulation in the liver, high
blood levels of octanoic acid, low blood glucose
(hypoglycemia), sleepiness, vomiting, and coma.
The pattern of organic acids in the urine helps in the
diagnosis of this disease: the urine commonly contains
high levels of 6-carbon to 10-carbon dicarboxylic acids
and low levels of urinary ketone bodies
Oksidasi Asam
Amino
Metabolic Fates of Amino Groups
 Asam amino akan mengalami transaminasi membentuk
glutamat
 Glutamat akan membebaskan gugus amino sebagai
suatu amoniak di dalam hati
 Amoniak
ditransportasikan
dalam bentuk
glutamin
 In metabolic acidosis (p. 652) there is an increase
in glutamine processing by the kidneys. Not all the
excess NH4+ thus produced is released into the
bloodstream or converted to urea; some is
excreted directly into the urine. In the kidney, the
NH4+ forms salts with metabolic acids, facilitating
their removal in the urine. Bicarbonate produced by
the decarboxylation of -ketoglutarate in the citric
acid cycle can also serve as a buffer in blood
plasma. Taken together, these effects of glutamine
metabolism in the kidney tend to counteract
acidosis.
Alanine Transports Ammonia from
Skeletal Muscles to the Liver
 Nitrogen Excretion and the Urea Cycle

If not reused for the synthesis of new amino acids or

other nitrogenous products, amino groups are channeled
into a single excretory end product
Most aquatic species, such as the bony fishes, are
ammonotelic, excreting amino nitrogen as ammonia.
Most terrestrial animals are ureotelic, excreting amino
nitrogen in the form of urea
birds and reptiles are uricotelic, excreting amino
nitrogen as uric acid
In ureotelic organisms, the ammonia deposited in the
mitochondria of hepatocytes is converted to urea in the
urea cycle. acid
The Citric Acid and Urea Cycles Can Be Linked
 The Activity of the Urea Cycle Is Regulated
at Two Levels
Pathways of Amino Acid Degradation
Six Amino Acids Are Degraded to Pyruvate
Seven Amino Acids Are Degraded to Acetyl-CoA
Five Amino Acids Are Converted
to -Ketoglutarate
Four Amino Acids Are Converted
to Succinyl-CoA
Strutur polipeptida (ptotein)
Monosakarida, disakarida,
polisakarida, glikobiologi
Monosakarida, disakarida, polisakarida, glikobiologi
amilosa
Liopolisakarida
Peptidoglikan
Asam Lemak
Gliserol dan Trigliserida
Asam amion, dipeptida oligopeptida dan polipeptida
(protein)
 Protein dan asam amino, uji,
metabolisme, disease
Karbohidrat, uji-uji, metabolisme
(glikolisis dan glukoneogenesi),
desease
Lipid, asam lemak, uji,
metabolisme, disease
Biosintesis karbohidrat pada
tumbuhan dan bakteri
Fosforilasi oksidatif dan fotoforilasi