Amino acids and proteins
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Amino acids and proteins

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Amino acids and proteins Amino acids and proteins Document Transcript

  • Keshava Pavan K, medical student, KMC, Mangalore, India AMINO ACIDS AND PROTEINSImportant 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
  • → 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
  •  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
  •  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
  •  + 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
  •  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
  •  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
  •  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: → TransaminationAlanine α ketoglutarate PLP ALTPyruvate glutamatePLP – pyridoxal phosphate; ALT – alanine transaminase/SGPT -serum glutamatepyruvate transaminase
  • → Trans deamination (transamination + deamination)Aspartate α ketoglutarate PLP ASTOxaloacetate 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 oxidaseL amino acid α keto acid + NH4+ FMN FMNH2 oxidaseD amino acid α keto acid + NH4+ FAD FADH2 → Non oxidative deaminationSerine pyruvate + NH4+ Serine dehydrataseThreonine α keto butarate + NH 4+ Threonine dehydratase
  • 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 DEFECIENCYHyperammonemia type I CPS IHyperammonemia type II OTCCitrullinemia ASSArgininosuccinic aciduria ASLHyperargininemia Arginase → Normal serum urea level: 20 to 40 mg/dL → Increase in serum urea level – uremia → Causes:
  •  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 PLPHistidine histamine + CO 2 Histidine decarboxylase5-hydroxy tryptophan 5-hydroxy tryptamine/ serotoninGlutamate γ amino butyric acid SIMPLEST AMINO ACID GLYCINE → Glucogenic → Non essential → Synthesis :
  • FH4 N5 N10 methylene FH4Serine glycine Serine hydroxy methyl transferase Threonine glycine + acetaldehyde Threonine aldolase → Catabolism: NAD+ NADH PLPGlycine CO 2 + NH4+ Glycine FH4 N5N10 methylene FH4 cleavage systemThe reverse reaction is used in synthesis of glycine. Enzyme is then named glycinesynthase.Deficiency of enzymes of glycine cleavage system causes non-ketotic hyperglycemiaGlycine serine pyruvate gluconeogenesis Serine dehydratase
  • NH4+ MalateGlycine glyoxalate Oxalate Glycine oxidase FormateBlock 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 +PiGlutamate + 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
  • Cholic acid + glycine glycocholic acidChenodeoxy cholic acid + glycine glyco chenodeoxycholic acidBenzoic 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 SAHGuanidoacetate creatine Guanidoacetate methyl transferaseNorepinephrine epinephrineNicotinamide N-methyl nicotinamide excreted in urine(detoxification/biotransformation reaction)
  • → 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 synthaseHomocysteine + serine cystathionine PLP H 2O cystathionase H 2O PLP Homoserine + cysteine
  • → Glucogenic pathwayHomoserine α keto butyrate propionic acid NH2 CO2 Glucogenic TCA cycle succinyl CoAMethionine α keto γ methiol butyrate α keto butyrate + methyl mercaptan (CH3 – SH) → Inborn errors of methionine metabolism: → Homocystinuria2 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
  • 2H2 cysteine cystine Cysteine reductase 2H → Biosynthesis: refer trans-sulphuration pathway under methionine. → Catabolism:  Transamination PLPCysteine mercaptopyruvate H 2S + pyruvate glucogenic α KG glu  cysteine desulphydratasecysteine + H2O pyruvate + NH 3 + H2S  cysteine dioxygenasecysteine cysteine sulfinic acid 2O2 2H2O α KG 2NADH 2NAD+ PLP Glu Sulfinyl pyruvate Desulfinase Pyruvate + sulphurous acid
  • 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. → DetoxificationBromobenzene 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
  • 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.
  • O2 H 2OPhenyl 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
  • This test is positive in other cases also, hence is only a screening test. → Tyrosine (para hydroxy phe ala) metabolism: transaminaseTyrosine parahydroxy phenyl pyruvate PLP O2 hydroxylase αKG glutamine CO2 Vit C homogentisic acidhomogentisate oxidase O2maleyl acetoacetate isomerase H 2Ofumaryl acetoacetate fumarate + acetoacetate hydrolase glucogenic ketogenicFunctions: → 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
  • Tyrosine hydroxylaseTyrosine Dihydroxy Phenyl Alanine (DOPA) Tetrehydrobiopterin dihydrobiopterin PLP DOPA decarboxylase NADP+ NADPH +H+ CO2 DopamineDopamine β hydroxylase, Cu2+ O2Nor epinephrine SAM methyl transferase SAHEpinephrine 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
  •  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+
  • 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 O2Tryptophan N-formyl kynurenine Tryptophan pyrrolase THFA Formyl THFA 1C pool Kynurenine when PLP is defecient3 hydroxy kynurenine xanthurenic acid Kynureninase H 2O PLP (VitB6) alanine glucogenic3 hydroxy anthranilic acid NICOTINIC ACID PATHWAY (3%) (97%) Quinolinate aminocarboxy muconaldehyde CO2Nicotinic acid (niacin) amino muconate aldehyde NH3Nicotinate mononucleotide (NMN) ketoadipate CO2Desamido NAD NAD+ acetyl CoA ketogenic
  • → Formation of serotonin: TryptophanNADP+ tetrehydrobiopterin tryptophan hydroxylase O2NADPH +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 ISOLEUCINEMetabolism:Valine leucine isoleucine PLP transaminaseαketo valenic acid αketo isocaproic acid αketo βmethyl valeric acid branched chain α keto acid dehydrogenaseisobutyryl CoA isovaleryl CoA α methyl butyryl CoA → Maple Syrup Urine Disease(MSUD)/branched chain ketonuria  1 in 100000  Convulsions
  •  Mental retardation  Coma, death  Onset at 1 month; death in 1 year. valine leucine isoleucine POLYAMINES → Putrescine → Spermidine → SpermineBiosynthesis: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.
  • 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-essentialBiosynthesis: 1. Any amino acid α keto glutarate α keto acid glutamate 2. Histidine, arginine, proline catabolism  glutamateCatabolism: NAD+ NADH + H+ 1. Glutamate α keto glutarate L-glutamate dehydrogenase (OXIDATIVE DEAMINATION) 2. By transamination reactions.
  • 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 → GlucogenicBiosynthesis:Glutamate + NH3  glutamineCatabolism:Glutamine glutamate + NH3 GlutaminaseFunctions: → Part of proteins and peptides → Transport of ammonia → Acid base balance → Synthesis of purines and pyrimidines → Conjugating agent.
  • Diagram (1)Diagram (2) Diagram (3) Diagram (4)
  • Diagram (5)Diagram (6)
  • Diagram (7)Diagram (8)
  • Diagram (9)Diagram (10)
  • Diagram (11) 