“Gomel State Medical University” Board of Biologic Chemistry Formulas, reactions, metabolic pathways and schemes in biologic chemistry Biochemistry of Proteins, Nucleic Acids. Biochemistry of Vitamins, and Hormones Manual for students Gomel, 2015 Contents 1. Biochemistry of proteins and nucleic acids Prot&NA-1 - Formulas of proteinogenic AA (essential and nonessential) – revising from 1st semester. - Scheme of "endogenous. AA pool "(the way of formation and utilization) - Gamma-glutamyl cycle (Meister’s Cycle) - Scheme of HCl synthesis, regulation of synthesis - Scheme of proteolysis in the gastrointestinal tract - Reactions of protein putrefaction (Tyr, Phe, Trp, Lys, Orn) - Detoxifying of protein putrefaction products: conjugation with UDP-glucuronate, PAPS Prot&NA-2 - Ammonia detoxification pathways - Amino acids catabolism / “entering” into TCA - Urea cycle Prot&NA-3 - Catecholamine synthesis - Creatine and SAM metabolism - Glutamate metabolism in Meister and Roberts (GABA-shunt) cycles - Protein, carbohydrate, and lipid metabolism integration Prot&NA-4 - “Replicative fork” scheme - Purine synthesis. Scheme of purine ring synthesis - Purine synthesis. Conversion of IMP into AMP and GMP - Pyrimidine synthesis Prot&NA-5 - Purine catabolism - Pyrimidine catabolism - Translation: scheme of protein synthesis (in prokaryotes) 2. Biochemistry of Vitamins and Hormones Vitamins - The structure of lipid- and water-soluble vitamins B1, B2, В3, В5 (PP), B6, В9, C, H, А, D2, D3, E, K, F. - The structure of NAD+, NADH, NADP+, NADPH, FAD, FADH2, FMN, FMNH2, TPP, pyridoxal phosphate, THF, coenzyme Q, 25-OH D3, 1,25-(OH)2 D3. Hormones-1 - The mechanism of metabolic regulation of adenylyl cyclase (scheme) - – revising from 1st semester. - Inositol-3-phosphate pathway of metabolism regulation (scheme) - – revising from 1st semester. - Synthesis of eicosanoids (scheme) - – revising from 1st semester. - Ca-P metabolism (scheme) - Metabolism of vitamin D - The principles of the neuroendocrine system organization (scheme) Hormones-2 - Structure of hormones: TRH, oxytocin, T3, T4, epinephrine, norepinephrine, cortisol, aldosterone, estradiol, testosterone, progesterone, serotonin TxA2, PGI2, LTB. - Thyroid hormones (T3, T4)synthesis - Synthesis of serotonin - Synthesis of catecholamines (repeat) 1. Biochemistry of proteins and nucleic acids Prot&NA-1 Scheme of "endogenous. AA pool "(the way of formation and utilization) excretion Glucose Ketone bodies urea -ketoacids NH3 Tissue proteins catabolism CO2,, H2O, ATP Luminal proteases Dietary proteins catecholamines AA derivatives with hormonal function Amino acids endogenous pool thyroxine Nitrogen containing protein compounds s si n tep a C Biosynthesis from carbohydrates Peptides Proteins biogenic amines hormones, nucleotides, heme, creatine Regulatory peptides Gamma-glutamyl cycle (Meister’s Cycle) R CH COOH NH2 AA outside -glutamyl transferase cell membrane R CO NH CH COOH CH2 -glutamyl-amino acid CH2 H2N CH COOH H2C SH CH CO NH CH2 COOH Cysteinyl-glycine NH2 Peptidase NH2 CH2 COOH glycine O N H H COOH 5-oxoproline 5-Oxoprolinase (3) ATP ATP H2C SH CH COOH NH2 cysteine R CH COOH NH2 AA inside -glutamylcyclotransferase (2) H2C SH CO NH CH CO NH CH2 COOH CH2 -glutamyl-cysteinyl-glycine (glutathione) CH2 H2N CH ADP + Рi COOH Glutathionesynthetase (6) ADP + Рi COOH CH2 CH2 H2N CH COOH Glutamic acid H2C SH CO NH CH COOH CH2 CH2 H2N CH COOH g-Glutamyl-cysteinsynthetase (6) -Glutamyl-cystein ADP + Рi ATP Scheme of HCl synthesis, regulation of synthesis Plasma Gastric lumen Parietal cell Glucose Pyruvate Carbonic CO2 anhydrase +H2O H2CO3 H+/K+ -ATPase K+ ATP TCA K+ H+ H+ ATP+Рi HCO3- HCO3- Cl- HCl Cl- Cl- Anion-transporter proteins Cloride channel Regulation: Prostaglandins Е Acetylcholine Histamine Gastrin R1 R2 R3 R4 M H2 EP3 CCK2 Gs-proteins Gi-proteins adenylate cyclase Ca2+ ATP cAMP Ca2+ Protein kinases K+ Omeprazole H+ Scheme of proteolysis in the gastrointestinal tract Protein digestion enzymes Serine proteases Ala Gly Ser O Tyr Phe Met Leu O Arg Lys O O H HN CHC N CHC O H O H HN CHC N CHC O H Elastase O H NH CHC N CHC O H Trypsin Chymotrypsin Trypsinogen Proelastase Metalloproteases Chymotrypsinogen Asparagine proteases Ala Val Ile Leu Arg Lys O Tyr Phe Leu O O H H2N CHC N CHC OH H O H H2N CHC N CHC OH H Pepsin Carboxypeptidase А Carboxypeptidase В H+ Pepsinogen Procarboxypeptidase А,В O O H H2N CHC N CHC OH H H Dipeptidase H2O O H2N CHC OH H + Glycine Caseine Rennin (chymosine) O H2N CHC OH H Glycine Ca2+ Paracaseine Glycopeptide H2N CH CH3 O C R Alanine aminopeptidase (liberates N-terminal alanine molecule) O H2N CH C CH2 CHCH3 CH3 R Leucine aminopeptidase (liberates any N-terminal amino acid) Reactions of protein putrefaction (Tyr, Phe, Trp, Lys, Orn) Detoxifying of protein putrefaction products: conjugation with UDP-glucuronate, PAPS HO Tyrosine CH2 CH COOH NH2 HO CH3 HO p-Cresol NH2 CH2 CH COOH Phenol CH3 N H Trypthophan N H Skatol Indol N H Indol Indoxyl PAPS O S O3K 3',5'-ADP N H Urine indicane 3-Indoxyl sulfate COOH H2N CO2 NH2 lysine H2N COOH H2N ornithine CO2 NH2 cadaverine H2N putrescine NH2 N O O HO S O P O O OH N CH2 O O O O P O O- NH2 alkanes, isoalkanes, +hydroxyderivatives NH2 COOH O N N BCAA (leu, ile, val) OH OH OH OH 3'-phosphoadenosine5'-phosphosulfate (PAPS) O O O P OH O HO P O O HN O CH2 N O OH OH Uridine diphosphate glucuronic acid (UDPGA) Prot&NA-2: Ammonia detoxification pathways Ammonia detoxification pathways transformation (Urea cycle) conjugation (nervous and muscular tissue) glutamine synthetase (6) Glu + ATP excretion (liver and kidney) Gln Gln + ADP + Pi glutaminase (3) H2O NH3 Asp + ATP NH3 NH4+ asparaginesynthetase (6) Gln Glu Asn Asn + ADP + Pi asparaginase (3) H2O Asp NH3 Glu NH4+ Amino acids catabolism /“entering” into TCA Glucose GNG CO2 Ala Ser Gly Cys Trp Thr Leu Trp Lys Phe Tyr COOH CO2 C O CH3 Pyruvate PEP CH3 O C CH3 S-CoA C O CH2 Acetyl-CoA O Asp Asn COOH H2C COOH O C S-CoA Acetoacetyl-CoA HO C COOH CH2 H2C COOH COOH Citrate Oxaloacetate COOH CH2 Phe Tyr Asp C H2C CH2 CH2 HOOC C H C COOH H Fumarate COOH HOOC C O -ketoglutarate C S-CoA O Ketone bodies Glu Gln His Pro Arg Succinyl-CoA COOH H3C CH C O S-CoA Methyl-malonyl-CoA H3C CH2 C O S-CoA Propyonyl-CoA Ile Val Met Thr Urea cycle: HOOC CH2 NADP+ R C COOH O -ketoacid CH2 CH COOH Glutamate NH2 Transaminase (2) Glutamate dehydrogenase (1) NADPH + Н+ R CH COOH NH2 -ketoglutarate 2 ATP + HCO3- + NH3 amino acid Mitochondrion Carbamoyl phosphate synthetase (6) H2N C OPO32- + 2 ADP + Pi O Carbamoyl phosphate O C NH2 Pi NH Ornithine NH3+ (CH2)3 HC NH3+ COOOrnithine Arginase (3) (CH2)3 Ornithine transcarbamoylase (2) CH NH3+ COOCitrulline Citrulline Aspartate AMP + PPi H2O H2N C NH2+ NH (CH2)3 HC NH3+ COOArginine H2O Argininosuccinate synthetase (6) COOCH2 Argininosuccinate lyase (4) COOCH CH COOFumarate NH C NH NH COO(CH2)3 ArgininoHC NH3+ succinate COOCH -ketoglutarate Aspartate amino transferase (2) Fumarase (4) COOCH2 HC OH COOMalate Total equation: Aspartate + NH3 + CO2 + 3 ATP CH NH3+ COO- ATP O H2N C NH2 Urea COOCH2 Malate DH (1) COOCH2 C O COOOxaloacetate Glutamate 3 H2O + Urea + Fumarate + 2 ADP + AMP + 2 Pi + PPi Prot&NA-3 Catecholamine synthesis CH2 COOH CH NH2 Phenylalanine HO CH2 COOH CH NH2 Phenylalanine-4 monooxygenase (1) O2 HO H2O Tyrosine HO Tyrosinehydroxylase (1) HO O2 Tyrosine COOH CH2 CH NH2 H2O COOH CH2 CH NH2 Dioxyphenylalanine (DOPA) DOPA Decarboxylase (4) HO HO OH CH CH2 NH2 Norepinephrine S-adenosylmethionine Phenylethanolamine-N-methyl transferase (2) S-adenosylhomocysteine HO HO OH CH CH2 NH CH3 Epinephrine Dopamine-hydroxylase (1) H2O O2 CO2 HO HO CH2 CH2 NH2 Dopamine Creatine and SAM metabolism ATP CH3 THFA S N5-CH3-THFA PPi+Pi CH2 CH2 HC Methyltransferase (2) Methionineadenosyltransferase (2) NH2 COOH Methionine NH2 N CH3 SH S CH2 CH2 CH2 CH2 N N CH2 O H H H H OH OH N CH NH2 H2N CH COOH COOH Homocysteine S-adenosylmethionine NH2 N Adenosine S H 2O CH2 CH2 HC N CH2 O H H H H OH OH N N Guanidylacetate methyltransferase (2) NH2 Ornithine S-adenosylhomocysteine HN C CH2 NH2 CH2 NH H2C COOH Guanidine acetate HN C NH2 N CH3 H2C NH NH NH2 COOH C COOH Creatine Glycine amidinotransferase (2) CH2 H2N CH COOH Arginine + NH2 CH2 COOH Glycine Glutamate metabolism in Meister and Roberts (GABA-shunt) cycles HOOC CH CH2 CH2 COOH NH2 Glutamate -glutamyl- cysteine-synthetase (6) ATP cysteine CO2 ADP + Pi CH2 CH2 CH2 COOH NH2 H2C SH CO NH CH COOH CH2 CH2 H2N CH COOH -glutamylcysteine ATP Glutathionesynthetase (6) Glutamatedecarboxylase (4) -aminobutyric acid (GABA) ketoacid GABA-aminotransferase (2) aminoacid glycine ADP + Pi H2C SH CO NH CH CO NH CH2 COOH CH2 -glutamylCH2 cysteyl-glycine H2N CH (glutathione) COOH O C CH2 CH2 COOH H Succinic semialdehyde H2O OH CH2 CH2 CH2 COOH NAD+ -oxybutyric acid (GOBA) NADH • H HOOC CH2 CH2 COOH Succinic acid + Protein, carbohydrate, and lipid metabolism integration Lipids (TG) Carbohydrates Fatty acids Glycerol Acetoacetyl-CoA Acetyl-CoA H2O Glucose Pyruvate TCA CO2 Ketogenic aminoacids Aminoacids Proteins Glycogenic aminoacids Prot&NA-4 “Replicative fork” scheme (By Berezov and Korovkin, 1998) 5' 3' DNA-gyrase dnaA и dnaB protein complexes Primosome DNA-helicase- Primase DNA-binding proteins 3' 3' Okazaki fragments 5' 5' Primer 3' 5' Leading strand DNA-polymerase III DNA-polymerase I catalyses cleavage of oligoribonucleotyde primer, and filling the formed gaps by deoxyribonucleotides. Primer removed Lagging strand DNA-polymerase I DNA-polymerase III catalizes elongation stage in DNA replication. DNA-ligase carries out the function of 2 DNA strand arrangement. DNA-helicase (rep-protein) functions by unwinding the DNA double helix. Primase catalyzes the synthesis of short oligoribonucleotide (primer) from where the DNA synthesis begins. DNA-gyrase takes part in the supercoiling, providing both: DNA replication and transcription. DNA-ligase Purine synthesis. Scheme of purine ring synthesis Respiratory CO2 H C Aspartate N C Glycine N CH HC 10 N -Formyltetrahydrofolate C N N H Amide nitrogen of glutamine N5,N10-Methenyltetrahydrofolate Purine synthesis. Conversion of IMP into AMP and GMP O HN IMPdehydrogenase (1) N H2O NAD+ N Asp O H2C O P OH OH GTP Inosinic acid (IMP) NADH + H+ O Mg2+ GDP + Pi N N N H Xanthylic acid ATP CH CH2 NH O H2C O P OH OH Gln Glu GMP COOH CH CH COOH Fumarate NH2 N N O H2C O P OH OH Adenylosuccinate lyase (4) O HN N Adenylosuccinic acid Mg COOH N N N 2+ GMPsynthetase (6) ADP + Pi H2N Adenylosuccinate synthetase (6) COOH HN O H2N CH COOH CH2 COOH N N N N O H2C O P OH OH N AMP GMP + ATP GDP + АDP GDP + ATP GTP + ADP N O H2C O P OH OH Pyrimidine synthesis CO2 + Gln Carbamoylphosphatesynthetase-II (6) ATP ADP H2N C O PO3H2 Carbamoyl- O + phosphate O Pi HO C H2N CH2 H2O O HN DihydroAspartate CH C orotase O trancarba- O N N COOH HOOC CH CH2 COOH moylase (2) H COOH (3) H Carbamoyl NH2 Dihydroorotic acid aspartate NAD+ Aspartate Dihydoorotate dehydrogenase (1) NADH+H+ O O O CO2 PPi PRPP HN HN HN Orotate N COOH O N COOH Orotate O O N phosphoH decarboxylase R-5-P Orotate rybosyl(4) R-5-P OMP transferase (2) UMP ATP UMP NADP+ kinase (2) NADP+H+ ADP UDP dUDP Ribonucleotide (deoxyuridine ATP reductase (1) diphosphate) UDP ADP kinase (2) dTMP ADP kinase (2) UTP ATP dUMP ATP+Gln H2O N5,N10-Methylene CTP Thymidylate synthase (6) H4 folate synthase (2) Pi ADP+Glu H2 folate NH2 O N CH3 HN O N O N R-5-P-P-P R-5-P-P-P CTP TMP Prot&NA-5 Purine catabolism O NH2 N N N Adenosine H2O H2N N Ribose H3PO4 Nucleoside phosphorylase (2) ribose-1phosphate O O N HN инозин N N Guanosine Ribose Adenosine deaminase (3) NH3 N HN N N H2N Ribose H3PO4 H2O Guanosine deaminase (3) NH3 O N HN N H Hypoxanthine N N H N Guanine Nucleoside phosphorylase (2) ribose-1phosphate N HN H2O + O2 O H2O2 N HN Xanthine oxydase (1) N N H H Xanthine O H2O + O2 Xanthine oxydase (1) H2O2 O HN O H N O N N H H Uric acid Pyrimidine catabolism: NH2 Cytidine deaminase (3) N O O O N Ribose O H2O NH3 O N Thymidine H2O thymidine phosphorylase (2) 2-deoxyribose1-phosphate 2-deoxyribose Ribose-1-phosphate O O HN O H3PO4 uridinenucleosidase (3) H3PO4 uridine phosphorylase (2) Ribose Deoxyribose Uridine H2O Uridinenucleoside (3) N Ribose Cytidine CH3 HN HN CH3 HN N H Uracyl O N H Thymine NADPH + H+ Dihydrouracyl dehydrogenase (1) NADP+ O O HN O CH3 HN N H O Dihydrouracyl H2O N H Dihydrothymine Dihydropyrimidinase (3) H2N C N CH2 CH COOH O H CH3 H2N C N CH2 CH2 COOH O H N-carbamoy- amino- H2O CO2 N-carbamoyl-aminoisobutyric acid propionic acid) H2O NH3 Urea H2N CH2 CH2 COOH -alanine NH3 CO2 H2N CH2 CH COOH CH3 -amino isobutyric acid Translation: scheme of protein synthesis (in prokaryotes) Biochemistry of Vitamins and Hormones Vitamins-1 Water-soluble vitamins O CH2 N H3C N NH2 CH3 N+ S CH2 CH2 OH Thiamin (B1) H3C N CH3 HO CH2 C CH C NH CH2 CH2 COOH CH3 OH O NH N O Panthothenic acid (B3) Riboflafin (B2) COOH N Nicotinamide Nicotinic acid, Niacin N HOH2C CH CH CH CH2 OH OH OH CONH2 N H3C HO H3C CH2OH CH2OH N H H2N N CH2 NH N Folic acid (B9) NH2 HO CH2OH H3C Pyridoxol H2C CH2OH H3C N Pyridoxal N Pyridoxamine Vitamin B6 OH N O HO Vitamin B5 (PP) N C C NH CH COOH CH2 O CH2 COOH HO CH2 HO CH O H N O HO OH Ascorbic acid (С) S O N H COOH Biotin (H) Vitamins: lipid-soluble -6 18 HOOC CH2OH 9 CH2 Linoleic acid 10 12 13 Retinol HO H Ergocalciferol (D2) HOOC Reitnal 5 6 10 8 9 Eicosapentaenic acid CH2 OH 4 5 7 12 11 8 10 13 12 15 14 11 13 18 16 15 14 16 17 18 17 19 20 20 22 HOOC O Docosahexaenic acid HO Retinoic acid Cholecalciferol (D3) Vitamin A Vitamin F Vitamin D O CH3 O CH3 HO CH3 CH3 O CH3 9 Linolenic acid O H3C -3 HOOC CH3 -Tocopherol (E) CH3 CH3 CH3 CH3 O OH CH3 CH3 CH3 Phylloquinone (K1) CH3 H O CH3 Menaquinone (K2) Vitamin K n OH Menadiol (K3) Coenzymes (1/2). NH2 C O O P O CH2 O O O P O CH2 H H OH OH O N N O N O H P O O OH OH CH2 H H NAD+ O N H3C N NH N H2C CH CH CH CH2 O OH OH OH O O P O OH NH2 N CH2 N O HO OH O NH2 N N O P O H N N O OH OH O H3C H3C N N H O O P O OH N CH2 N O FAD HO OH H NADP N O N O H N N FADH2 O H3C N H3C N H2C CH CH CH CH2 O OH OH OH O P OH OH FMN N P O O CH2 H NADPH NH O H N O H3C N N H H2C CH CH CH CH2 O OH OH OH OH N NH2 N O H OH O O P O O H3C O P OH NH2 C O N H OH O O P O O H OH OH O N O NH2 O P OH CH2 + NH H2C CH CH CH CH2 O OH OH OH O O P O CH2 O NH2 N H H N O OH OH O H N N N O O P O CH2 O NADH H3C O P OH N NH2 N O O P O CH2 O O OH OH O H N NH2 C O NH2 H C O NH FMNH2 O N N Coenzymes (2/2). CH3 N H3C OH N+ NH2 N S H OH CH2 CH2 O P O P OH O O HO H3C Thiamin diphosphate C O CH2 H3C H3C H N C NH CH COOH CH2 O N CH2 H Tetrahydrofolate (THF) COOH N H2N N N Pyridoxal phosphate O O OH O O P OH OH CH2 NH Derivatives of vitamin D with hormonal effect CH3 H O O CH3 6-10 CH2 Coenzyme Q (ubiquinone) HO OH OH CH2 HO Calcidiol, 25-ОН D3 Calcitriol, 1,25-(ОН)2 D3 OH Hormones-1 Ca/P metabolism Metabolism of vitamin D The principles of neuroendocrine system organization Hormones-2 Structure of hormones OH O O H H2C C C NH CH C H2C NH CH2 C O HN N CH C O NH2 OH I I I O I N OH I I HO Epinephrine (adrenaline) Estradiol Thyrotropin-releasing hormone (TRH) CH2 H-Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-CO-NH2 S S Oxytocin HO HC NH2 COOH COOH CH2OH CO OH HO CH2 HC NH2 Tetraiodothyronine (thyroxine; T4) CH CH2 NH CH3 OH HO O I HO N H HO CH2 CH2 NH2 HO Serotonin triiodothyronine (T3) Norepinephrine (noradrenaline) CH3 CO OH CH CH2 NH2 OH O CH2OH CO HO O O Cortisol O Testosterone Progesterone O O COOH O CH3 OH OH Thromboxane A2 Aldosterone OH OOC COO CH3 O OH Prostacycline (PGI2) CH3 OH Leukotriene B Serotonin synthesis H2N CH COOH CH2 tetrahydrobiopterine N H Tryptophan O2 H2O tryptophan hydroxylase (1) dihydrobiopterine CH H2N COOH CH2 HO N H CO2 5-Hydroxytryptophan cyclic amino acids decarboxylase (4) CH2 CH2 NH2 HO N H Serotonin Thyroid hormones (T3, T4)synthesis 1 Iodine uptake 2 Oxidase NH2 I2 + HO CH2 CH COOH 4 Dehalogenase Tyrosine Tyrosine iodinase I Free MIT NH2 HO CH2 CH COOH MIT, monoiodotyrosine I Free DIT NH2 HO CH2 CH COOH I DIT, diiodotyrosine 3 Condensating enzyme I Free Т3 Protease HO I O CH2 CH COOH I I Free Т4 Protease HO I O I NH2 Triiodothyronine (T3) NH2 CH2 CH COOH I Tetraiodothyronine (thyroxine; T4)