chapter 6 - kaunsalamoudi.kau.edu.sa/getfile.aspx?id=196004&lng=ar… · ppt file · web...

2009 Cengage-Wadsworth

Chapter 6

Protein


Functional Categories

• Catalysts - enzymes– Hydrolases - cleave compounds– Isomerases - transfer atoms in a molecule– Ligases (synthases) - join compounds– Oxidoreductases - transfer electrons– Transferases - move functional groups



• Messengers – Hormones

• Structural elements– Contractile proteins– Fibrous proteins– Globular proteins

• Immunoprotectors– Immunoproteins (antibodies)



• Transporters– Albumin– Transthyretin (prealbumin)– Transferrin– Ceruloplasmin– Lipoproteins



• Buffers– Regulation of acid-base balance

• Fluid balancers– Proteins attract water to blood

• Other roles– Adhesion, signaling, receptors, storage– Conjugated proteins

• Glycoproteins• Proteoglycans


Protein Structure & Organization

• Primary structure– Sequence of covalent bonds among amino acids

• Secondary structure– Hydrogen bonding– -helix– -conformation or -pleated sheet– Random coil

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Protein structure Each protein has a unique shape or conformation. all proteins

are composed exclusively of subunits of amino acids, which join together in long chains called polypeptides that fold or coil into

the unique shape of the functional protein

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1-Primary structure of proteinsamino acids sequences • The primary structure of a protein simply

consists of its linear sequence of amino acids; for example, "alanine-glycine-tryptophan-serine-glutamate-asparagine-glycine-lysine-…

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2-Secondary structure

• As peptide bonds are formed, aligning the amino acids, hydrogen bonds form between different amino acids in the chain.

• This bonding coils the polypeptide into the secondary structure of the protein, most commonly the alpha helix,

• The α-helix coils at every 4th amino acid.

http://commons.wikimedia.org/wiki/File:1GZX_Haemoglobin.png

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2-Secondary structure The α-helix coils of protein

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Pleated Proteinthe polypeptide have portions that lie parallel to each other (held by hydrogen bonds) instead of in the alpha helix, in which

the amino acids’ hydrogen bonds form a pleated structure. Fibrous proteins have significant pleated structures


Protein Structure & Organization• Tertiary structure

– Clustering of hydrophobic AAs toward center– Electrostatic (ionic) attraction– Strong covalent bonding between cysteine residues -

disulfide bridges• Quaternary structure

– Interactions between 2 or more polypeptide chains– Oligomers

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3-Tertiary Structure of protein• the side chains (the R groups) of amino acids may fold

independently into a functional unit called the domain.

• Domains are connected by the rest of the polypeptide. • The folding of a protein into its domains is related to

the hydrophilic or hydrophobic properties of its amino acids.

• Domain formation is part of the tertiary structure or proteins. globular shape (globulin)

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Tertiary Structure of protein

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4-Quaternary Protein Structure the structure formed by several protein molecules (polypeptide chains), usually called protein subunits

• If two or more polypeptide chains join in aggregate, they form a quaternary structure, such as in the protein molecule, hemoglobin.

• Often quaternary proteins are complexed with a different molecule, often a mineral. Hemoglobin contains iron, for example.

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4-Quaternary Protein Structure

Haemoglobin structure


Amino Acid Classification

• Structure– Central C– At least 1 amino group (NH2) – At least 1 carboxy (acid) group (COOH)– Side chain (R group)

• Makes AA unique

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Amino acid the building block

of proteins


Amino Acid Classification

• Net electrical charge– Zwitterions have none– Zwitterions: ion with a positive and a negative

charge• Polarity

– Polar or nonpolar– Determined by R group

• Essentiality– Lysine, threonine & histidine totally indispensable

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the carboxyl group is stronger acid than the amino group. At physiological pH (around 7.4) the carboxyl group will be unprotonated and the amino group will be protonated.

An amino acid with no ionizable R-group would be electrically neutral at this pH. This species is termed a zwitterion.

An amino acid in its (1) un-ionized and (2) zwitterionic forms

http://en.wikipedia.org/wiki/File:Amino_acid_zwitterions.svg

Amino Acid classification based on polarity

27- 21

Non-Polar

Polar

UnchargedCysteineProlineSerine

GlutamineAsparagine

HydrophobicTryptophan

PhenylalanineIsoleucineTyrosineLeucineValine

Methionine

AmbivalentGlycine

ThreonineAlanine

ChargedArginine (+)

Glutamic acid (-)Aspartic Acid (-)

Lysine (+)Histidine (+)

Essential AA Nonessential AAHistidine AlanineIsoleucine Arginine **Leucine AsparagineLysine Aspartic AcidMethionine Cysteine **Phenylalanine Glutamic acidThreonine Glutamine **Tryptophan Glycine **Valine Proline **

SerineTyrosine **


Sources of Protein

• Exogenous sources– Animal products - except fats– Plant products - grains/grain products, legumes,

vegetables• Endogenous proteins

– Desquamated mucoasal cells– Digestive enzymes & glycoproteins


Digestion & Absorption

• Protein digestion– Mouth & esophagus - none– Stomach

• HCl denatures• Pepsin hydrolyzes peptide bonds


Digestion & Absorption– Small intestine

• Pancreatic enzymes– Trypsinogen trypsin– Chymotrypsinogen chymotrypsin– Procarboxypeptidases A & B carboxypeptidases– Proelastase– Collagenase

• Brush border peptidases– Aminopeptidases, dipeptdylaminopeptidases, tripeptidases

• Tripeptides hydrolyzed or absorbed at brush border



• Intestinal brush border membrane amino acid & peptide absorption– Amino acid transport

• Carriers required - passive & active transporters– Peptide transport

• PEPT1 • Co-movement of protons (H+)



• Intestinal basolateral membrane transport of amino acids– Diffusion & sodium-independent transport are

main modes• Intestinal cell amino acid use

– Cells use or partially metabolize for release into blood



– Intestinal glutamine metabolism• Primary energy source for enterocytes

– Intestinal glutamate metabolism– Intestinal aspartame metabolism– Intestinal arginine metabolism– Intestinal methionine & cysteine metabolism



• Amino acid absorption into extraintestinal tissues– AAs enter portal vein to liver– Transport into hepatocytes– Transport into other cells– -glutamyl cycle


Amino Acid Metabolism

• Metabolism of AAs includes:– Protein synthesis– Amino acid catabolism– Hepatic catabolism

• Uses of aromatic amino acids• Uses of sulfur-containing amino acids• Uses of branched-chain amino acids• Uses of other amino acids

– Plasma amino acids & pools

Nitrogen Pool


Synthesis of Plasma Proteins, Nitrogen-Containing Nonprotein Compounds, & Purine & Pyrimidine Bases

• Plasma proteins– Albumin– Transthyretin (prealbumin)– Retinol-binding protein– Blood clotting proteins– Immunoproteins– Transport proteins– Acute phase proteins– Stress (heat) shock proteins (hsp)



• Nitrogen-containing nonprotein compounds– Glutathione - antioxidant, reacts with H2O2, AA

transport, conversion of prostaglandin H2 to D2 & E2

– Carnitine - FA transport– Creatine - part of phosphocreatine (high-energy

compound)



– Carnosine - may be antioxidant– Choline - methyl donor, part of acetylcholine &

lecithin & sphingomyelin



• Purine & pyrimidine bases– Main constituents of DNA & RNA– Pyrimidines

• 6-membered rings containing N in positions 1 & 3• Uracil, cytosine & thymidine

– Purines• 2 fused rings, N in positions 1, 3, 7, 9• Adenine & guanine


Amino Acid Catabolism Overview

• Transamination &/or deamination of amino acids– Deamination = removal of amino group– Transamination = transfer of amino group from

one AA to AA carbon skeleton or -keto acid• Catalyzed by aminotransferases

OVERVIEW OF AMINO ACID METABOLISM

ENVIRONMENT ORGANISM

Ingested protein

Bio- synthesis Protein

AMINO ACIDS

Nitrogen Carbonskeletons

Urea

Degradation (required)

1 2 3

a

b

PurinesPyrimidinesPorphyrins

c c

Used for energy

pyruvateα-ketoglutaratesuccinyl-CoAfumarateoxaloacetate

acetoacetateacetyl CoA

(glucogenic)(ketogenic)


Amino Acid Catabolism Overview• Disposal of ammonia--the urea cycle

– NH3 combines with CO2 or HCO3- to form carbamoyl

phosphate– Carbamoyl phosphate reacts with ornithine

transcarbamoylase (OTC) to form citruline– Aspartate reacts with citruline to form argininosuccinate– Arginosuccinate is cleaved to form fumarate & arginine– Urea is formed and ornithine is re-formed from cleavage of

arginine

Steps of Urea Synthesis (cont...)

• Formation of urea & ornithine

http://en.wikipedia.org/wiki/File:Amino_acid_zwitterions.svg


Amino Acid Catabolism Overview• An overview of metabolism of the carbon

skeleton/-keto acid– Energy generation– Glucose & ketone body production– Cholesterol production– Fatty acid production

FATE OF THE CARBON SKELETONS

Carbon skeletons are used for energy.

Glucogenic: TCA cycle intermediates

or pyruvate (gluconeogensis)

Ketogenic: acetyl CoA, acetoacetyl CoA,

or acetoacetate

Transamination


Hepatic Catabolism & Uses of Aromatic Amino Acids

• Phenylalanine & tyrosine– Phenylalanine converted to tyrosine by phenylalanine

hydroxylase– Tyrosine

• Degradation begins with transamination to p-hydroxyphenylpyruvate

• Tyrosine used in other tissues for synthesis of L-dopa & catecholamines

• Melanin, thyroid hormones– Disorders of phenylalanine & tyrosine metabolism


Hepatic Catabolism & Uses of Aromatic Amino Acids

• Tryptophan– Catabolized to N-formylkynurenine– This is catabolized to formate & kynurenine– Used for:

• Protein synthesis • Energy, glucose, & ketone body production• Synthesis of serotonin & melatonin

– Disorders of tryptophan metabolism.


Hepatic Catabolism & Uses of Sulfur (S)-Containing Amino Acids

• Methionine– Converted to S-adenosyl methionine

• SAM is principal methyl donor• Removal of methyl group yields S-adenosyl homocysteine (SAH)

– SAH converted to homocysteine– Homocysteine reacts with serine to form cystathionine– Cystathionine cleaved to form cysteine & -ketobutyrate– Propionyl CoA (made from -ketobutyrate) converted to D-

methylmalonyl CoA– Disorders of methionine metabolism


Hepatic Catabolism & Uses of Sulfur (S)-Containing Amino Acids

• Cysteine– Used for protein & glutathione synthesis– Converted to cysteine sulfinate, used to produce taurine– Taurine important in retina, functions as bile salt & inhibitory

neurotransmitter– Cysteine degradation yields pyruvate & sulfite


Hepatic Catabolism & Uses of the Branched-Chain Amino Acids

• Isoleucine, leucine, & valine• Taken up & transaminated primarily in

muscles


Hepatic Catabolism & Uses of Other Amino Acids

• Lysine– Ketogenic - catabolism yields acetyl CoA– Disorders of lysine metabolism

• Threonine– 3 pathways– Disorders of threonine metabolism


Hepatic Catabolism & Uses of Other Amino Acids

• Glycine & serine– Produced from one another in reversible reaction

requiring folate– Disorders of glycine metabolism

• Arginine– Kidney - creatine synthesis– Liver - generation of urea & ornithine

• Histidine– Glutamate, carnosine, histamine


Amino Acids Not Taken Up by the Liver: Plasma Amino Acids & Amino Acid Pool(s)

• Plasma concentrations rise after a meal• Pool of about 150 g of endogenous +

exogenous AAs • Re-use thought to be primary source of AAs

for protein synthesis• More nonessential than essential in pool


Interorgan “Flow” of Amino Acids & Organ-Specific Metabolism

• Glutamine & the liver, kidneys, & intestine– Ammonia transport– Hypercatabolic conditions

• Alanine & the liver & muscle– Inter-tissue transfer of amino groups– Liver: converted to glutamate or glucose



• Skeletal muscle– Isoleucine, leucine, & valine– Nitrogen-containing compounds as indicators of

muscle mass & muscle/ protein catabolism



• Kidneys– Serine synthesis from glycine– Glycine catabolism to ammonia– Histidine generation from carnosine degradation– Arginine synthesis from citruline– Tyrosine synthesis from phenylalanine– Guanidoacetate formation from arginine & glycine for

creatine synthesis


Brain & Accessory Tissues• Biogenic amines & neurotransmitters/hormones

– Tryptophan - melatonin & serotonin– Tyrosine - dopamine, norepinephrine, epinephrine– Glysine - inhibitory neurotransmitter– Taurine - inhibitory neurotransmitter– Aspartate - excitatory neurotransmitter– Glutamate - excitatory neurotransmitter or converted to -

amino butyric acid (GABA)


Brain & Accessory Tissues

• Neuropeptides– Hormone-releasing factors– Endocrine effects– Modulatory actions on transmitter functions,

mood or behavior– Neurosecretory cells of hypothalamus secrete– Synthesized from AAs via DNA codes


Protein Turnover: Synthesis & Catabolism of Tissue Proteins

• Food intake & nutritional status• Hormonal mediation• AA pools connect 2 cycles of N metabolism:

– Protein turnover– Nitrogen balance

• Protein synthesis & degradation controlled separately


Protein Turnover: Synthesis & Catabolism of Tissue Proteins

• Cellular protein degradation systems– Lysosomal degradation– Proteasomal degradation– Calcium or calcium-activated proteolytic

degradation


Changes in Body Mass with Age• Lean body mass increases throughout childhood

– Changes in total fluid & ECF/ICF• Gender differences develop during adolescence

– Greater increase in males• After 25, weight gain = fat gain• Lean mass decreases with increasing age

– More so in women than men– Body water declines too


Protein Quality & Protein Intake

• Foods can be categorized as:– High-quality or complete proteins– Low-quality or incomplete proteins

• Evaluation of protein quality– Nitrogen balance/nitrogen status– Chemical or amino acid score– Protein digestibility corrected amino acid score



– Protein efficiency ratio– Biological value– Net protein utilization– Net dietary protein calories percentage

• Protein information on food labels– % Daily Value



• Recommended protein & amino acid intakes– RDA for adults = 0.8 g/kg– AI for birth-6 months– RDA for indispensible AAs – Negative effects of high protein intakes

controversial (no UL)– AMDR = 10%-35% kcal



• Protein deficiency/malnutrition– Kwashiorkor

• Adequate energy with insufficient protein• Edema owing to loss of blood proteins

– Marasmus• Wasting, emaciation• Chronic insufficiency of energy & protein


Perspective 6

Protein Turnover:Starvation Compared with Stress


Starvation vs. Stress• Starvation

– Protein synthesis decreases– Hormone balance adjusts– Adaptation - muscle catabolism slows

• Stress– Hypermetabolism– Lipolysis doesn’t lead to ketosis– Muscle catabolism undiminished– Protein turnover - immune response & acute phase

response

chapter 6 - kaunsalamoudi.kau.edu.sa/getfile.aspx?id=196004&lng=ar… · ppt file · web...

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