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The
Meaning
the
Based on the fact : The most abundant compound found in any dried living matter or cell (the 2nd after water) 1. They provide 12-20% of the total daily body energy requirement 2. Composed of 50-70% of the cells dry weight
logically, the most abundant compound should have the most important function
PROTEINS
Macromolecules
composed of polymers of covalently linked amino acids that are involved in every cellular process.
PROTEINS
Synthesized
in the liver and secreted by the hepatocyte into the circulation except immunoglobulins (plasma cells)
PROTEINS
All
proteins consist of polymers that are folded into specific conformations conformation plus the chemistry of wellplaced functional groups control a protein's function (another example of function follows form) are made up of 20 different types of amino-acid monomers
This
Proteins
PROTEIN
A
It
is digested firstly in the stomach, and then in the duodenum to dipeptides and amino acid. using active transport with
Absorbed
sodium.
Stored
PROTEIN METABOLISM
FUNCTIONS:
1.
2.
3. 4.
5. 6. 7.
Repair body tissues Important in blood coagulation Immunologic function For transport of metabolic substances (bec. They are soluble substances) Maintenance of osmotic pressure Maintenance of blood pH (buffers) Biocatalysts
USES: PROTEIN SYNTHESIS The synthesis of new proteins is very important during growth.
In
adults new protein synthesis is directed towards replacement of proteins as they are constantly turned over.
of a variety of other compounds Examples of compounds synthesized from amino acids include purines and pyrimidines (components of nucleotides), catecholamines (adrenaline and noradrenalin) & neurotransmitters (serotonin)
as
a biological fuel - About 10% of energy production in humans is from amino acids
TYPES OF PROTEINS
Type Structural Contractile Transport Storage Hormonal Enzyme Protection Examples tendons, cartilage, hair, nails muscles hemoglobin milk insulin, growth hormone catalyzes reactions in cells immune response
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CLASSIFICATION OF PROTEINS
1. Simple Proteins 2. Conjugated Proteins
CLASSIFICATION OF PROTEINS
1.
Simple Proteins
Contain
peptide chains w/c on hydrolysis yield only amino acids in shape fibrous (fibrinogen, troponins, collagen) globular (hemoglobin, plasma proteins, enzymes, peptide hormones)
Based
CLASSIFICATION OF PROTEINS
2. Conjugated Proteins Comprise of a protein (apoprotein) and non protein moiety (prosthetic group) These proteins impart certain characteristics to the proteins
CLASSIFICATION OF PROTEINS
1.
2.
Lipoproteins
3.
Glycoproteins
4.
Mucoproteins or proteoglycans
5.
Nucleoproteins
Amino acids - molecules containing an aminegroup, a carboxylic acid group and a side-chain that varies between different amino acids. Peptide - two or more amino acids that are put together by peptide bond. Protein - a functional, polypeptide chain composed of at least around fifty amino acids put together. Peptide bond -the bond that connects amino acids together
proteins are unbranched polymers of amino acids linked head to tail, from carboxyl group to amino group, through formation of covalent peptide bonds, a type of amide linkage. bond formation results in the release of H2O.
Peptide
The peptide backbone of a protein consists of the repeated sequence ONOCOCO, where N represents the amide nitrogen C is the -carbon atom of an amino acid in the polymer chain
the final C is the carbonyl carbon of the amino acid, which in turn is linked to the amide N of the next amino acid down the line.
It determines the identity of protein, molecular structure, function binding capacity and recognition ability
Any change in the amino acid composition can significantly alter the protein
Refers to specific 3-dimensional conformationsalpha helix, beta pleated and bend form
4. Quaternary structure Is the association of 2 or more polypeptide chains to form a functional protein molecule Albumin have no quaternary structure (single polypeptide chain)
PROTEIN CONFORMATION
The overall three-dimensional architecture of a protein. This term is not to be confused with configuration, which denotes the geometric possibilities for a particular set of atoms
In going from one configuration to another, covalent bonds must be broken and rearranged.
In contrast, the conformational possibilities of a molecule are achieved without breaking any covalent bonds.
Fibrous proteins are in their secondary structure, which could be in the alpha helix or beta pleated forms. They are made of a repeated sequence of amino acids that can be coiled tightly around in a pattern that makes it a very strong structure.
Two examples are keratin (in hair and skin) and collagen (in tendons, cartilage, and bones).
Globular proteins are in their tertiary or quaternary structure, which is folded, creating a globular, threedimensional shape. Two examples are all enzymes and microtubules (form centrioles, cilia, flagella, and cytoskeleton).
AMINO ACIDS
Building
blocks of proteins
Carboxylic
acid group Amino group Side group R gives unique characteristics R side chain I H2HC COOH I H
30
I.
-AMINO ACIDS
Naturally occurring amino acids has an amino group (NH2) to the carboxyl group (COOH). They are bifunctional and classified as: a. Neutral: having equal number of amino and carboxyl group. b. Acidic: two carboxyl and one amino group.
c.
AMINO ACIDS
Amino
acids are organic acids containing an amine group. most common amino acids are alphaamino acids and the most common amino acids are the L- alpha-amino acids.
The
AMINO ACIDS
amino 1.
acid structure:
Rare
AMINO ACIDS
amino 2.
acid structure:
Side groups (labelled "R" ) are what distinguish the amino acids from each other.
groups can be nonpolar (hydrophobic), polar, acidic, or basic
ZWITTERIONS
3.
substances containing equal numbers of positive and negative charge due to their carboxyl and amine groups, which can be negatively and positively charged, respectively.
Several
common amino acids found in cells, such as ornithine and citrulline, are not used to make proteins.
Amino acids are used in three ways in the body : 1. Protein synthesis 2. Synthesis of a variety of other compounds 3. As a biological fuel
Protein synthesis The synthesis of new proteins is very important during growth. In adults new protein synthesis is directed towards replacement of proteins as they are constantly turned over.
Synthesis of a variety of other compounds Ex: purines and pyrimidines (components of nucleotides) catecholamines (adrenaline and noradrenalin) neurotransmitters (serotonin) histamine porphyrins (central oxygen binding component of Hb).
Amino acids are used in three ways in the body : As a biological fuel About 10% of energy production in humans. The % is much higher in carnivores, whose diet is almost protein.
PEPTIDE BONDS
Amino acids are the monomeric units or "building blocks" of proteins that are joined together covalently in peptide bonds. Amino acids are built into proteins by the process of translation using the genetic code.
PEPTIDE BONDS
enzyme pepsin, a family of enzymes that cleave these bonds and so break up protein chains;
pepsin is derived from the Greek root peptos, meaning cooked. Pepsin was one of the first enzymes to be prepared in pure form.
A peptide bond is a chemical bond formed between two molecules when the carboxyl group of one molecule reacts with the amino group of the other molecule, releasing a molecule of water (H2O). This is a dehydration synthesis reaction (also known as a condensation reaction), and usually occurs between amino acids.
Attached to the repetitive backbone are different kinds of appendages, the side chains of the amino acids. Backbone = -N-C-C-N-C-C-NPolypeptide is not quite synonymous with protein.
Making a polypeptide chain The relationship is somewhat analogous to that between a long strand of yarn and a sweater of a particular size and shape that one can knit from the yarn.
A functional protein is not just a polypeptide chain, but one or more polypeptides precisely twisted, folded, and coiled into a molecule of unique shape. It is the amino-acid sequence of a polypeptide that determines what three-dimensional conformation the protein will take.
conformation determines how it works. In almost every case, the function of a protein depends on its ability to recognize and bind to some other molecule. The surface chemistry of a protein is determined by the chemistry of exposed amino-acid R groups The interior of proteins is held together by R-group-to-R-group and backbone-tobackbone interactions
FORMATION OF A PEPTIDE
1.According to capability of our body to synthesize any given aa 2.According to physicochemical nature of R groups
1.Essentials aa an aa is considered essential if it can not be synthetized by the body - it must be supplied by the food 2.Nonessentials aa all the aa that can be synthesized by the body - not in food
54
Amino acids differ on the bases of side chain residues, donated as R The 20 different chemical groups can fall in three major categories with respect to their water solubility; Non polar residues Polar neutral residues Polar charged residues
1. 2. 3.
amino acids have non-polar (neutrally charged) R groups. amino acids have R chains with polar groups (charged either positive or negative).
Polar
amino acids - make the proteins hydrophilic (able to dissolve in water) amino acids - more hydrophobic (less soluble in water)
non-polar
fold themselves
the
hydrophobic ones are on the inner side allow hydrophilic molecules and ions to pass in and out of the cells through the channels they form.
These
channels are vital passages for many substances in and out of the cell.
lysine (+), arginine (+), aspartate (-) and glutamate (-). serine, threonine, asparagine, glutamine, histidine and tyrosine. alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophane, cysteine and methionine,
A.A.
GLYCINE
The amino acid glycine does not have a side chain and is hard to assign to a certain class. However, glycine is often found on the surface of the protein tertiary structure in loop regions and provides additional flexibility to these regions.
Charged: Arginine - Arg - R Lysine - Lys - K Aspartic acid - Asp - D Glutamic acid - Glu - E
Polar (may participate in hydrogen bonds): Glutamine - Gln - Q Asparagine - Asn - N Histidine - His - H Serine - Ser - S Threonine - Thr - T Tyrosine - Tyr - Y Cysteine - Cys - C Methionine - Met - M Tryptophan - Trp - W
Hydrophobic (normally buried inside the protein core): Alanine - Ala - A Isoleucine - Ile - I Leucine - Leu - L Phenylalanine - Phe - F Valine - Val - V Proline - Pro - P Glycine - Gly - G
O
Polar ll R = CH2OH, CH2SH, CH2CNH2, (polar groups with O-, -SH, -N-)
Non-polar
Polar neutral
Polar charged
enzymes are the prime movers in protein digestion just as they were in carbohydrate digestion. proteinases or proteases - enzymes for protein digestion Proteins are broken apart by the protein-digesting enzymes in a process called hydrolysis.
Duodenum - pancreatic protein enzymes, trypsin , chymotrypsin Instestine Blood Liver Muscle
Figure 25.15
Figure 25.17
Figure 25.3
PROTEIN METABOLISM
1. nitrogen equilibrium 2. biosynthesis of proteins 3. biosynthesis of NPN compounds & urea 4. Degradation of amino acids 5. metabolism of the carbon skeletons of amino acids
PROTEIN METABOLISM
NITROGEN POOL
Major dietary source of N is Protein (>95%), since the diet has very few free amino acids 2 AA are used for Protein Synthesis & N containing compounds 3 AA in excess are degraded (used for energy) N is disposed of in urea (80%), ammonia, uric acid or creatinine in urine with small amounts in fecal matter (undigested)
1
a. Negative nitrogen balance -when protein catabolism exceeds anabolism -excessive tissue destruction such as burns, wasting disease, high fever and starvation
b. Positive nitrogen balance -anabolism is greater than catabolism -growth, pregnancy and repair processes
1. Stress
2. Decreased Intake
3. Lack of an essential AA
1. Stress
2. Decreased Intake
3. Lack of an essential AA
NITROGEN BALANCE
CO
(found as part of peptidic bond) NH (also part of peptidic bond) R group (acidic, basic, hydrophylic and hydrophobic)
1.Same charge repel each other 2.Opposite charge attract each other 3.Hydrophobic moieties aggregate each other and avoid water and hydrophilic molecules or moieties.
Results :
-
Various geometric pattern in segment or part of polypeptide / protein molecule (secondary structure) as well as in the whole molecule itself (tertiary structure)
Note: The
sole determinant of primary str (aa sequence) is the gene. once it is formed, it can not be changed any more Only change in gene can change 1 aa on a protein mutation
Note:
On
the other hand, the higher structures are very susceptible to the environment variations, especially pH & to :
- The higher str is easier to be changed by environment than the lower str
BIOLOGICAL FUNCTION
Determined
Change
BIOLOGICAL FUNCTION
Denaturation : loss of 3D str (=tertiary str or conformation) result of any environmental modification 1. pH 2. To 3. organic solvent 4. heavy metals such Pb, Cd, Hg 5. uv or x-ray 6. physical treatment
Always conduct to decrease or even loss of specific biological activity or function of the protein. More severe denaturation result in decrease of the protein solubility.
* 2 Geometric forms of the global structure (3 D or tertiary structure) of protein : There are only 2 Each 3 D strc indicates the general function of any protein. The 3 D str: - Globular protein : proteins whose ratio horizontal axe : vertical axe are between 1 2 - Globular proteins are regulator protein (enzyme,mediator,transporter etc) - Fibrous protein : the ratio are >10 - Fibrous proteins are structural or supporter protein (collagen,keratin etc)
If a protein has > 1 secondary structure, then it is a globular protein. Consequently, it is regulator protein
- On the contrary, if it is consisted only of 1 secondary protein, then it is a fibrous protein. Consequently, it is a structural or support protein -
Change in 1 aa (primary str) will change the local interaction between adjacent R group change in second str tertiary str perturbation or even loss of biological (i.e. in sickle cell anemia)
ENVIRONMENT
ORGANISM
Ingested protein
1
Biosynthesis 2 3
Protein
a AMINO ACIDS c
Degradatio n (required) Nitrogen (ketogenic)
b c
Purines Pyrimidines Porphyrins
Carbon skeletons (glucogenic) Used for energy pyruvate -ketoglutarate succinyl-CoA fumarate oxaloacetate
Urea
acetoacetate acetyl CoA
PROTEIN BIOSYNTHESIS
Protein synthesis is the process in which cells build or manufacture proteins. used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA, which is then used as input for translation.
a) keto acids are funneled into the Krebs cycle (glucogenic/ketogenic) b) NH4+ is cleared via urea, NH4+, with uric acid however major product is urea (80%) c) Creatine/creatinine important for energy consideration
1.
2.
classes of waste products: nitrogenous Urea uric acid creatinine non-nitrogenous carbon dioxide water
UREA CYCLE
Function: To provide a way to dispose of the amino groups from amino acids during their metabolism. Location: Liver, kidney Regulation: Primarily by availability of amino groups and ammonia
UREA CYCLE
Connections:
From amino groups of amino acids through glutamate and glutamate dehydrogenase
From amino groups of amino acids through aspartate and argininosuccinate synthase From ammonia through carbamoyl phosphate synthetase To urea
UREA CYCLE
OXIDATIVE DEAMINATION
The first step in amino acid catabolism is the removal of the nitrogen (the amino group).
DEGRADATION
OF AMINO ACIDS
1. 2. 3.
DEGRADATION
OF AMINO ACIDS
Decarboxylation 1. a chemical reaction that releases carbon dioxide (CO2). 2. Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain.
DEGRADATION
Transamination
OF AMINO ACIDS
Accomplished by enzymes called transaminases or aminotransferases. This process is an important step in the synthesis of some non-essential amino acids (amino acids that are not supplied from the diet). The chirality (property of assymetry) of an amino acid is determined during transamination.
DEGRADATION
OF AMINO ACIDS
Transamination 1. or aminotransfer 2. The first is the reaction between an amino acid and an alpha-keto acid. 3. The amino group is transferred from the former to the latter; 4. this results in the amino acid being converted to the corresponding -keto acid, while the reactant -keto acid is converted to the corresponding amino acid (if the amino group is removed from an amino acid, an -keto acid is left behind).
DEGRADATION
Transamination
OF AMINO ACIDS
DEGRADATION
OF AMINO ACIDS
Oxidative deamination a form of deamination that generates oxoacids in the liver. In Urea cycle Glutamate is the only amino acid that undergoes rapid oxidative deamination by using glutamate dehydrogenase which uses NAD or NADP as a coenzyme. This process leads to 2 toxic products: 1. Hydrogen Peroxide 2. Ammonia.
OXIDATIVE DEAMINATION
Molecular Biochemistry II
Amino acids, when deaminated, yield -keto acids that, directly or via additional reactions, feed into major metabolic pathways (e.g., Krebs Cycle).
Amino acids are grouped into 2 classes, based on whether or not their carbon skeletons can be converted to glucose:
glucogenic ketogenic.
pyruvate, or
These are
Glucogenic amino acids are the major carbon source for gluconeogenesis when glucose levels are low. They can also be catabolized for energy, or converted to glycogen or fatty acids for energy storage.
acetyl-CoA, or acetoacetate.
Acetyl CoA, & its precursor acetoacetate, cannot yield net production of oxaloacetate, the gluconeogenesis precursor. For every 2-C acetyl residue entering Krebs Cycle, 2 C leave as CO2. Carbon skeletons of ketogenic amino acids can be catabolized for energy in Krebs Cycle, or converted to ketone bodies or fatty acids. They cannot be converted to glucose.
Glycogenic
Ketogenic
Alanine, Arginine Asparagine, Aspartate Cysteine, Glutamate Glutamine, Glycine Histidine, Methionine Proline, Serine Threonine, Valine
Leucine Lysine
PRODUCTS OF AMINO ACID DEGRADATION Ala to pyruvate by transamination Arg to urea and glutamate Asp to oxaloacetate by transamination or to fumarate via urea cycle Asn to Asp Cys carbon to pyruvate, sulfur to sulfate Glu to -ketoglutarate by transamination, then to glucose Gln to glutamate by hydrolysis Gly to glyoxylate or serine His to glutamate and one-carbon pool Met to propionyl-CoA via homocysteine cystathionine ketobutyrate Pro to glutamate Ser to glycine and CH2THfolate
PRODUCTS OF AMINO ACID DEGRADATION Ser to glycine and CH2THfolate Thr to propionyl-CoA through ketobutyrate Val to propionyl-CoA through transamination, decarboxylation, and a bunch of rearrangements Leu to acetoacetate and acetyl-CoA through transamination, decarboxylation, and a bunch of rearrangements Ile to propionyl-CoA through transamination, decarboxylation, and a bunch of rearrangements Phe to Tyr, then to acetoacetate and fumarate Tyr to acetoacetate and fumarate Try to acetyl-CoA via ring oxidation and cleavage to ketoadipate Lys to acetyl-CoA via transamination and deamination to ketoadipate
Instead of being properly broken down into amino acids, small amounts of whole or partial proteins are absorbed into the blood.
The body wants amino acids, not whole proteins, and whole proteins are viewed by the system as an enemy.
AMINOACIDOPATHIES
AMINOACODOPATHIES
Inherited
Exists
in either the activity of a specific enzyme in the metabolic pathway or in the membrane transport system for amino acids
A. ALKAPTONURIA an inborn error of metabolism characterized by the absence of homogentisate oxidase in the tyrosine pathway
B.
HOMOCYSTINURIA
results to elevated levels of homocysteine and methionine in blood and urine clinical features: physical defects, thrombosis, osteoporosis, eye lens abnormality, mental retardation
C.
it is characterized by markedly reduced or absence of -ketoacid decarboxylase results to accumulation of branched-chain amino acids (leucine, isoleucine and valine) in blood, urine and CSF 4mg/dL of leucine is indicative of MSUD Clinical features: failure to thrive, muscular rigidity, mental retardation, hupoglycemia
D.
PHENYLKETONURIA (PKU)
an autosomal recessive trait characterized by the deficiency of the enzyme phenylalanine hydrolase (PAH)/phenylalanine-4-mono-oxygenase, which catalyzes the conversion of phenylalanine to tyrosine Phenylpyruvic acid (prime metabolite) is present in both blood and urine in elevated concentration Clinical features: retarded mental development (infants and children) Diagnostic indicators: >1200 umol/L of phenylalanine in blood; musty odor of urine
E.
TYROSINEMIA
it is characterized by deficiency of either of these enzymes: tyrosine amino transferase (tyrosinemia II); 4hydroxyphenylpyruvic acid oxidase (tyrosinemia III); fumarylacetoacetate FAA hydrolase (tyrosinemia I)
accompanied by elevated methionine and phydroxyphenylpyruvic acid in blood deficiency of these enzymes would lead to liver damage or cirrhosis.