Amino acids and proteins

1. Keshava Pavan K, medical student, KMC, Mangalore, India AMINO ACIDS AND PROTEINS Important points → All amino acids in body are l- amino acids → Dextro/laevo form of amino acid is decided by –NH2 group → There are amino acids other than the 20 but they are not found in proteins (as they are not coded) → Above mentioned amino acids come under DERIVED AMINO ACIDS → Hydroxyproline, hydroxylysine, γ-carboxyglutamic acid, N- Formyl methionine are derived amino acids found in proteins → L-ornithine, citrulline, GABA, homoserine, homocysteine, histamine are derived amino acids not found in proteins → Non- alpha amino acids: β-alanine, GABA, δ-aminolevulinic acid, taurine → D- amino acids: Actinomysin D, gramicidin, polymyxin, valinomysin → Proteins in lipid environment have non-polar amino acids → At isoelectric pH, amino acids have least mobility, minimum solubility & least buffering action → Histidine is a very good buffer in the body as its pI (7.6) is close to blood pH → Histidine is found mainly in hemoglobin → A biologically active protein has atleast a 3D structure → Collagen is most abundant protein in human body → STRUCTURES OF COLLAGEN IN DIFFERENT PLACES  Vitrious humour- dispersed as gel to stiffen structure  Tendons- bundled in tight parallel fibers to provide tensile strength  Cornea- stacked to transmit light with minimum scattering  Bone- → Parallel arrangement is quarter staggered

2. → Osteogenesis imperfecta: replacement of glycine → GLUTATHIONE  Tripeptide  Maintains RBC membrane structure integrity  Protects Hb from oxidation by H2O2  detoxification → Substance- P  Decapeptide  Neurotransmitter → Denaturating agents  Physical: heat, violent shaking, X-rays, UV rays  Chemical: acid, alkali, organic solvents, heavy metal salts, urea, salicylate → Denaturation of ribonuclease by urea is reversible → Denatured protein cannot be crystallised → Complete proteins: egg albumin, milk proteins → Partially incomplete proteins: rice & wheat proteins (no Lys, Thr) → Incomplete proteins: gelatin (Trp), zein (Trp, Lys) → TDM : Therapeutic Drug Monitering → Functional classification  Structural – keratin, collagen, elastin  Catalytic – enzymes  Transport – Hb, albumin, transferrin  Hormonal – insulin, GH  Contractile – actin, myosin  Storage – ferritin, myoglobin

3.  Genetic – nucleoprotein  Immune – immunoglobulins (Igs)  Receptor – for hormones, viruses etc.  Plasma proteins – albumin, globulin, fibrinogen, prothrombin → Total plasma protein concentration : 6-8 g/dL → Albumin – 3.5 – 5.5 g/dL → Globulin – 1.8-3.6 g/dL → Fibrinogen – 0.2- 0.4 g/dL → Types of globulins → α1 globulin  Retinal binding protein (RBP) (binds with Vit A & transports it)  α1 fetoprotein  α1 antitrypsin  apolipoprotein A → α2 globulin  ceruloplasmin  transcortin  haptoglobin → β globulin  β-hemopexin  transferrin  C-reactive protein → γ globulin  immunoglobulins → Albumin  50-60% of plasma proteins

4.  Simple, globular protein  Synthetized in hepatocytes  Half life of 15- 20 days  Undergoes degradation- pinocytosis → Functions:  Osmotic pressure regulation  Blood volume & blood pressure regulation  Transportation (of mainly bilirubin, fatty acid, Ca2+, Cu2+, drugs like aspirin, sulphonamides, steroid hormones)  Nutritive → Disorders:  Hypoalbuminemia: • Malnutrition • Malabsorption • Liver cirrhosis & other liver disorders • Excess loss during nephrotic syndrome and other kidney diseases, surgery & haemorrhage • Overhydration/hemodilution  Analbuminemia: • Genetic • Types are homozygous & heterozygous → Pre albumin – two parts: thyroxine binding pre albumin binds thyroxine; retinal binding pre albumin binds retinal – theses two are found in 1:1 ratio and are together called transthyretin → Acute phase proteins (APP)  Plasma proteins that change in concentration due to acute phase reactions(APR).  2 types – positive & negative

5.  + increases during APR. e.g,. α1 antitrypsin, haptoglobin, ceruloplasmin, CRP  - decreses during APR. e.g,. pre-albumin, albumin, transferrin → Causes for acute phase reactions Injury/infection/cancer Inflammation Positive response Negative response ↑cytokines ↑vasoactive substances ↑interleukins alter vascular permiability ↑positive APP movement of plasma proteins from plasma to ECF → α1 antitrypsin prevents elastase from degrading elastin in lungs. → If α1 antitrypsin is deficient – exposed to smoke – met-sulphoxide formed – emphysema (therefore more in smokers) → C Reactive protein – binds to C-polysaccharide present on pneumococci → Ceruloplasmin  Glycoprotein  Binds to 6 molecules of copper

6.  Binds to 90% of Cu2+ in blood circulation  Blue coloured  Ferrous to ferric  Deficiency- WILSON’S DISEASE (hepato-lenticular degeneration –refer MINERALS – COPPER)  Normal concentration- 25 to 50 mg/dL → IMMUNOGLOBULINS  Synthesized by plasma cells  Glycoprotein  Tetramer of 2 light & 2 heavy chains  Constant & variable region  Hyper-variable regions – 3 in light chain, 4 in heavy chain. → Structure – refer diagram (1) → Hydrolysis at hinge region – refer diagram (2) → Types of light chains  Kappa (K)  Lambda (λ) → Types of heavy chains  gamma, γ (IgG)  Alpha, α (IgA)  Mu, µ (IgM)  Delta, δ (IgD)  Eta, ε (IgE) → Individual structures – refer diagram (3) → Functions of Igs: → IgG

7.  70% of Igs  Secondary immune response  Only Ig to cross placental barrier thus providing protection to fetus.  Neutralisation of toxins from antigenic cells  Enhances activity of complement proteins  Prepares cell for phagocytosis (opsonisation) → IgA  20% of Igs  Found in body fluids  Mucus & body secretions  Surface immunity → IgM  8 – 10%  Primary response  Phagocytosis → IgD  Less than 1%  Surface receptor  Not much known because it is very labile → IgE  0.004%  During allergy, binds to mast cell & basophil, rupturing their membranes releasing histamine. (- hypersensitivity) → Multiple myeloma  Malignant proliferation of plasma cells → BENCE JONES PROTEIN

8.  Low molecular weight proteins  Produced excessively during Multiple myeloma & other disorders  Excreted in urine. → Digestion of proteins → In stomach  HCl  acidic pH helps to activate pepsinogen to pepsin  denaturation  protection against bacteria  pepsin  rennin in infants → endopeptidase and exopeptidase activity – refer diagram (4) → in intestine  pancreatic enzymes – secretin, cholecystokinin  intestinal enzymes – trypsin, chymotrypsin, carboxypeptidase A and B, elastase → Absorption of proteins – refer diagram (5) → Glutathione: γ glutamyl cycle/Meister cycle - refer diagram (6) General reactions of amino acids: → Transamination Alanine α ketoglutarate PLP ALT Pyruvate glutamate PLP – pyridoxal phosphate; ALT – alanine transaminase/SGPT -serum glutamate pyruvate transaminase

9. → Trans deamination (transamination + deamination) Aspartate α ketoglutarate PLP AST Oxaloacetate glutamate NAD+/NADP+ Oxidative demination in liver glutamate dehydrogenase NADH+ H+/NADPH+ H+ α ketoglutarate + NH4+ AST – aspartate transaminase/SGOT serum glutamate oxaloacetate transaminase → Oxidative deamination oxidase L amino acid α keto acid + NH4+ FMN FMNH2 oxidase D amino acid α keto acid + NH4+ FAD FADH2 → Non oxidative deamination Serine pyruvate + NH4+ Serine dehydratase Threonine α keto butarate + NH 4+ Threonine dehydratase

10. Cysteine pyruvate + H 2S + NH4+ Cysteine desulphydratase Glutamine synthetase Glutamate + NH4+ glutamine In liver glutaminase ATP ADP + Pi glutamate + NH 4+ In muscles in liver Glucose pyruvate alanine pyruvate Glu α KG glu α KG α KG + NH4+ UREA → Urea cycle – refer diagram (7) → Disorders related to urea cycle DISORDER DEFECIENCY Hyperammonemia type I CPS I Hyperammonemia type II OTC Citrullinemia ASS Argininosuccinic aciduria ASL Hyperargininemia Arginase → Normal serum urea level: 20 to 40 mg/dL → Increase in serum urea level – uremia → Causes:

11.  Pre-renal • Vomiting, diarrhoea • Excessive degradation of proteins (as in DM) • Major surgery  Renal • Nephrotic syndrome • Other kidney diseases  Post-renal • Renal stones • Prostate gland enlargement → Decarboxylation reactions PLP Histidine histamine + CO 2 Histidine decarboxylase 5-hydroxy tryptophan 5-hydroxy tryptamine/ serotonin Glutamate γ amino butyric acid SIMPLEST AMINO ACID GLYCINE → Glucogenic → Non essential → Synthesis :

12. FH4 N5 N10 methylene FH4 Serine glycine Serine hydroxy methyl transferase Threonine glycine + acetaldehyde Threonine aldolase → Catabolism: NAD+ NADH PLP Glycine CO 2 + NH4+ Glycine FH4 N5N10 methylene FH4 cleavage system The reverse reaction is used in synthesis of glycine. Enzyme is then named glycine synthase. Deficiency of enzymes of glycine cleavage system causes non-ketotic hyperglycemia Glycine serine pyruvate gluconeogenesis Serine dehydratase

13. NH4+ Malate Glycine glyoxalate Oxalate Glycine oxidase Formate Block in the reaction forming formate leads to increased oxalate in urine (hyperoxaluria) causing urolithiasis, nephrocalcinosis. → Biologically important products formed from glycine:  Glutathione  Creatine → Glutathione: γ - glutamyl cysteinyl glycine ATP ADP +Pi Glutamate + cysteine glutamyl cysteine Glutamyl cysteine synthetase ATP Glycine glutathione synthetase ADP +Pi Glutathione → Creatine – refer diagram (8) → Functions of glycine:  Synthesis of glutathione, creatine  Component of proteins. Eg., in collagen, every third amino acid is glycine (X – Y – Gly)n  In heme synthesis – for details refer PORPHYRINS chapter  In conjugation

14. Cholic acid + glycine glycocholic acid Chenodeoxy cholic acid + glycine glyco chenodeoxycholic acid Benzoic acid + glycine hippuric acid → Disorders:  Non ketotic hyperglycemia  Primary hyperoxaluria  Glycinuria – due to defective reabsorption in nephron. SULPHUR CONTAINING AMINO ACIDS METHIONINE → Glucogenic → Essential → Functions:  Component of proteins and peptides  Coded by initiator codon  In transmethylation reactions → Synthesis of functional form SAM – refer diagram (9) → N-methylation: SAM SAH Guanidoacetate creatine Guanidoacetate methyl transferase Norepinephrine epinephrine Nicotinamide N-methyl nicotinamide excreted in urine (detoxification/biotransformation reaction)

15. → O-methylation: SAM SAH N-acetyl serotonin O-methyl N-acetyl serotonin/melatonin SAM SAH Epinephrine metanephrine Catechol O-methyl transferase → For summary of methionine refer diagram (10) → Deficiency of cobalamin leads to folate trap → Important reactions of methionine: → Trans-sulphuration pathway: Cystathionine synthase Homocysteine + serine cystathionine PLP H 2O cystathionase H 2O PLP Homoserine + cysteine

16. → Glucogenic pathway Homoserine α keto butyrate propionic acid NH2 CO2 Glucogenic TCA cycle succinyl CoA Methionine α keto γ methiol butyrate α keto butyrate + methyl mercaptan (CH3 – SH) → Inborn errors of methionine metabolism: → Homocystinuria 2 homocysteine homocystine excreted in urine  Mental retardation  Osteoporosis  Intravascular clotting  Ectopia lentis  High methionine in serum  Due to deficiency of either cystathionine synthase or methyl transferase → Cystathioninuria  Deficiency of cystathionase  Mental retardation CYSTEINE → Non essential → Glucogenic → It exists as cystine

17. 2H 2 cysteine cystine Cysteine reductase 2H → Biosynthesis: refer trans-sulphuration pathway under methionine. → Catabolism:  Transamination PLP Cysteine mercaptopyruvate H 2S + pyruvate glucogenic α KG glu  cysteine desulphydratase cysteine + H2O pyruvate + NH 3 + H2S  cysteine dioxygenase cysteine cysteine sulfinic acid 2O2 2H2O α KG 2NADH 2NAD+ PLP Glu Sulfinyl pyruvate Desulfinase Pyruvate + sulphurous acid

18. Functions: → Component of proteins and peptides  -SH group of glyceraldehyde 3 PO4 dehydrogenase is from cysteine  Tertiary and quaternary structures of proteins result from disulfide linkages between cysteine residues as in insulin, immunoglobulins.  Keratin has high concentration of cysteine  Collagen does not have cysteine. → Component of glutathione  Glutathione is called a pseudopeptide as peptide bond is between γ-carboxyl group and α-amino group instead of α-carboxyl group.  All peculiar properties of glutathione are due to –SH group of cysteine. 2 G-SH G-S-S-G → Thioethanolamine of CoASH  Components of coenzyme A are • Pantothenic acid (pantoic acid + β alanine) • β mercapto ethanolamine/thioethanolamine • AMP • Pyrophosphate  The thioethanolamine component is derived from cysteine. → Detoxification Bromobenzene mercapturic acid cysteine of glutathione → Formation of taurine  Primary bile acids – cholic acid, chenodeoxy cholic acid  Conjugated by glycine and taurine  Primary conjugated bile acids formed – glycocholic acid, taurocholic acid, glycochenodeoxy cholic acid, taurochenodeoxy cholic acid  These combine with sodium or potassium to form bile salts – sodium glycocholate, potassium glycocholate, sodium taurocholate, potassium taurocholate, sodium glycochenodeoxy cholate, potassium

19. glycochenodeoxy cholate, sodium taurochenodeoxy cholate and potassium taurochenodeoxy cholate.  Formation of taurine from cysteine: refer diagram (11) Inborn errors of cysteine metabolism: → Cystinuria/ cystinelysinuria → Cystinosis  Cystine storage disorder  Cystine accumulates in tissues  Deficiency of cystine reductase  Death in first 10 years of life. Important: → 4 amino acids are excreted in urine  Cystine  Ornithine  Arginine  Lysine → These have common reabsorptive pathway → These have 2 –NH2 groups at almost same distance between → Among these, cystine is most insoluble, hence may form calculi. AROMATIC AMINO ACIDS PHENYL ALANINE AND TYROSINE → Phe Ala essential, tyr non essential → Both glucogenic and ketogenic → Functions of phenyl alanine:  Proteins and peptides  Converted to tyrosine which has further actions.

20. O2 H 2O Phenyl alanine tyrosine phe ala hydroxylase activity I tetrahydrobiopterin dihydrobiopterin phe ala hydroxylase activity II (dihydrobiopterin reductase) NADP+ NADPH + H+  Alternate pathway: phe ala phe pyruvate (has keto gp.) phe lactate phe acetate DETOXIFICATION glutamine phe acetyl glutamine → Disorder: phenyl ketonuria  Phenyl alanine hydroxylase deficiency  During this, above mentioned alternate pathway takes place leading to ketone bodies in urine  1 in 10000  If proper screening is done it is supposed to be 1 in 1500  Diagnosis: • Serum phe ala level: normal <1 mg%, in this disorder, >20 mg% • FeCl3 test FeCl3 + urine green colour presence of phenyl pyruvate

21. This test is positive in other cases also, hence is only a screening test. → Tyrosine (para hydroxy phe ala) metabolism: transaminase Tyrosine parahydroxy phenyl pyruvate PLP O2 hydroxylase αKG glutamine CO2 Vit C homogentisic acid homogentisate oxidase O2 maleyl acetoacetate isomerase H 2O fumaryl acetoacetate fumarate + acetoacetate hydrolase glucogenic ketogenic Functions: → Component of proteins and peptides → Melanin synthesis (from melanocytes) Tyrosine DOPA dopaquinone Tyrosinase, Cu2+ tyrosinase, Cu2+ melanin Quinones of indole hallochrome polymerization spontaneous → Biosynthesis of catecholamines – dopamine, norepinephrine, epinephrine

22. Tyrosine hydroxylase Tyrosine Dihydroxy Phenyl Alanine (DOPA) Tetrehydrobiopterin dihydrobiopterin PLP DOPA decarboxylase NADP+ NADPH +H+ CO2 Dopamine Dopamine β hydroxylase, Cu2+ O2 Nor epinephrine SAM methyl transferase SAH Epinephrine metanephrine O-methylation Vanillyl Mandelic Acid (VMA) (3- methoxy 4-hydroxy mandelic acid) • Tumours of adrenal medulla, phaeochromocytoma produces high catecholamine levels leading to increased VMA production. → Synthesis of thyroid hormones T3 and T4  Synthesized in follicular cells of thyroid  Thyroglobulin has 5000 amino acids, out of which 115 are tyrosine and 35 can be iodinated. Inborn errors of tyrosine metabolism: → Alkaptonuria  Deficiency of homogentisate oxidase  1 in 25000

23.  Alkapton is formed from homogentisate, that deposits on connective tissue resulting in ochronosis.  Later, may suffer from arthritis  NO mental retardation  Diagnostic tests: • Urine allowed to stand in urine tube – blackening of urine from above downwards due to oxidation of homogentisic acid. • Positive Benedict’s test • FeCl3 test – green/blue colour. → Albinism  Deficiency of tyrosinase  1 in 20000  Prone to skin cancers. → Tyrosinemia type I (tyrosinosis)  Hepatorenal tyrosinemia  Deficiency of fumaryl acetoacetate hydrolase  Treatment – diet poor in phenyl alanine and tyrosine → Tyrosinemia type II (Richner Hanhart syndrome)  Occulocutaneous tyrosinemia  Deficiency of tyrosine transaminase  Formation of palmar keratosis, corneal lesions. → Neonatal tyrosinemia  Deficiency of parahydroxy phenyl pyruvate hydroxylase TRYPTOPHAN → Indolyl alanine (indole nucleus = benzene +pyrrole rings) → Essential amino acid → Both glucogenic and ketogenic → Products formed:  Serotonin  Melatonin  NAD+

24. Tryptophan metabolism:It has 11 carbon structure. Out of these 11 C,  1C – formyl group – 1C pool  3C – alanine – glucogenic  4C – acetoacetate – ketogenic  3C – as 3 CO2 O2 Tryptophan N-formyl kynurenine Tryptophan pyrrolase THFA Formyl THFA 1C pool Kynurenine when PLP is defecient 3 hydroxy kynurenine xanthurenic acid Kynureninase H 2O PLP (VitB6) alanine glucogenic 3 hydroxy anthranilic acid NICOTINIC ACID PATHWAY (3%) (97%) Quinolinate aminocarboxy muconaldehyde CO2 Nicotinic acid (niacin) amino muconate aldehyde NH3 Nicotinate mononucleotide (NMN) ketoadipate CO2 Desamido NAD NAD+ acetyl CoA ketogenic

25. → Formation of serotonin: Tryptophan NADP+ tetrehydrobiopterin tryptophan hydroxylase O2 NADPH +H+ dihydrobiopterin H 2O 5 hydroxy tryptophan PLP aromatic amino acid CO2 decarboxylase 5 hydroxy tryptamine (5 HT/ serotonin)  Serotonin is excreted as 5 hydroxy indole acetic acid BRANCHED CHAIN AMINO ACIDS VALINE, LEUCINE AND ISOLEUCINE Metabolism: Valine leucine isoleucine PLP transaminase αketo valenic acid αketo isocaproic acid αketo βmethyl valeric acid branched chain α keto acid dehydrogenase isobutyryl CoA isovaleryl CoA α methyl butyryl CoA → Maple Syrup Urine Disease(MSUD)/branched chain ketonuria  1 in 100000  Convulsions

26.  Mental retardation  Coma, death  Onset at 1 month; death in 1 year. valine leucine isoleucine POLYAMINES → Putrescine → Spermidine → Spermine Biosynthesis: Ornithine putrescine spermidine spermine SAM as propylamino group donor and not as methyl donor. Functions: → Production of initiation factors for translation → Cell proliferation → Stabilization of ribosomes and DNA → Synthesis of DNA and RNA → Growth factors, particularly in cell culture systems. Clinical significance: → Increased in cancer tissues → Excretion in urine is increased in cancer.

27. BIOGENIC AMINES → Produced by decarboxylation of amino acids or their products. → Decarboxylases and PLP are needed. 1. Histidine  histamine 2. Ornithine  putrescine 3. 5 hydroxy tryptophan  5 hydroxy tryptamine/serotonin 4. DOPA  dopamine In intestines by bacteria: 5. Tyrosine  tyramine 6. Glycine  GABA GLUTAMIC ACID → Acidic → Glucogenic → Non-essential Biosynthesis: 1. Any amino acid α keto glutarate α keto acid glutamate 2. Histidine, arginine, proline catabolism  glutamate Catabolism: NAD+ NADH + H+ 1. Glutamate α keto glutarate L-glutamate dehydrogenase (OXIDATIVE DEAMINATION) 2. By transamination reactions.

28. Functions: → Component of proteins – mainly gives negative charge → Synthesis of glutathione → Synthesis of GABA → Transport of ammonia → γ carboxy glutamate synthesis  in blood clotting factors II, VII, IX, X  post-translational modifications  Vit K needed → Osteocalcin → N acetyl glutamate GLUTAMINE → Amide of glutamate → Non-essential → Glucogenic Biosynthesis: Glutamate + NH3  glutamine Catabolism: Glutamine glutamate + NH3 Glutaminase Functions: → Part of proteins and peptides → Transport of ammonia → Acid base balance → Synthesis of purines and pyrimidines → Conjugating agent.

29. Diagram (1) Diagram (2) Diagram (3) Diagram (4)

30. Diagram (5) Diagram (6)

33. Diagram (11) 

Amino acids and proteins

Amino acids and proteins

Amino acids and proteins

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