متابوليسم چربيها
advertisement
متابولیسم چربیها Introduction Cholesterol Phospholipid Triglycerides Bile Salts T G Emulsion Lipase Fatty acids +Monoglycrid+Diglycrid <10 carbone Absorbed > 10 C in Intestine Cells with cholesterol &phspholipid &M.G &D.G& Protein Chylomicrones Breakdown of Triacylglycerols The lipases break the triacylglycerols down to fatty acids and glycerol The fatty acids are transportred in the blood by serum albumin Transport into Mitochondrial Matrix Acyl-CoA Synthetase Fatty acid oxidation Acyl-CoA Synthetase ATP Yield درهرمرحله یک FADH2تولید میشودکه در زنجیر انتقال الکترون 2ATPمیدهد . درهرمرحله یک NADH2تولید میشودکه در زنجیر انتقال الکترون 3ATPمدهید. درهرمرحله یک استیل کوآنزیم آ تولید میشودکه در سیکل کربس 12ATPمیدهد. پس در هر مرحله بتااکسیداسیون 17ATPتولید میشود. اگر اسید چرب 2nکربن در ساختمان آن باشد واکنشهای بتا اکسیداسیون n-1مرتبه تکرار میشود .بنابراین خواهیم داشت. چون در پایان دو استیل کوآداریم ودومی 12ATPتولید میکند ATP=17(n-1)+12 وچون در ابتدا 2ATPمصرف شد .بنابراین: ATP=17(n-1)+10 ATP=17n – 7 اگر تعداد کربن اسید چرب فرد باشد 3 .کربن ازاسید چرب کم کرده وطبق باال عمل نموده ودر پایان 6ATPبه آن اضافه میکنیم. اگر تعداد کربن اسید چرب فرد باشد 3 .کربن ازاسید چرب کم کرده ازرابطه زیر استفاده میکنیم ATP= 17n-1 . (جدید)محاسبه انرژی سوختن چربیها درهرمرحله یک FADH2تولید میشودکه در زنجیر انتقال الکترون ATP1/5میدهد . درهرمرحله یک NADH2تولید میشودکه در زنجیر انتقال الکترون ATP2/5مدهید. درهرمرحله یک استیل کوآنزیم آ تولید میشودکه در سیکل کربس ATP10میدهد. پس در هر مرحله بتااکسیداسیون ATP 14تولید میشود. اگر اسید چرب 2nکربن در ساختمان آن باشد واکنشهای بتا اکسیداسیون n- 1مرتبه تکرار میشود .بنابراین خواهیم داشت. چون در پایان دو استیل کوآداریم ودومی ATP10تولید میکند ATP=14(n-1)+10 وچون در ابتدا 2ATPمصرف شد .بنابراین: ATP=14(n-1)+8 ATP=14n – 6 اگر تعداد کربن اسید چرب فرد باشد 3 .کربن ازاسید چرب کم کرده وطبق باال عمل نموده ودر پایان 5ATPبه آن اضافه میکنیم. اگر تعداد کربن اسید چرب فرد باشد 3 .کربن ازاسید چرب کم کرده ازرابطه زیر ATP= 14n-1 استفاده میکنیم . Ketone Bodies Use of fatty acids in the citric acid cycle requires carbohydrates for the the production of oxaloacetate. During starvation or diabetes, OAA is used to make glucose Fatty acids are then used to make ketone bodies (acetoacetate and D–3–hydroxybutarate) ترکیبات ستونی -1استو استیک اسید. -2بتا هیدرکسی بوتیریک اسید. -3استون هرگاه اختاللی در متابولیسم کربوئیدراتها ایجاد شود استیل کوآ حاصل از سوختن چربیها چون نمی تواند وارد سیکل کربس شود جمع میشود وبا همدیگر ترکیب وتولید ترکیبات ستونی میکند. مواقع ایجاد؟ -1در قحطی ها وگرسنگی های شدید. -2در دیابت -3 -4 Fatty Acid Synthesis. Fatty acid are synthesized and degraded by different pathways. Synthesis takes place in the cytosol. Intermediates are attached to the acyl carrier protein (ACP). In higher organisms, the active sites for the synthesis reactions are all on the same polypeptide. The activated donor in the synthesis is malonyl– ACP. Fatty acid reduction uses NADPH + H+. Elongation stops at C16 (palmitic acid) بیو سنتز اسید های چرب Acyl Carrier Protein The intermediates in fatty acid synthesis are covalently linked to the acyl carrier protein (ACP) Citrate Shuttle Acetyl–CoA is synthesized in the mitochondrial matrix, whereas fatty acids are synthesized in the cytosol Acetyl–CoA units are shuttled out of the mitochondrial matrix as citrate: Eicosanoid Hormones Eicosanoid horomones are synthesized from arachadonic acid (20:4). Prostaglandins 20-carbon fatty acid containing 5-carbon ring Prostacyclins Thromboxanes Leukotrienes contain three conjugated double bonds 6.2 Eicosanoid Hormones Cholesterol: What is it? Cholesterol is a fatty steroid made primarily in the liver of most animals and humans. It is an integral component in the synthesis of hormones, can also be found in cell walls of animals and humans. Isolated cholesterol is a white, flaky solid that is insoluble in aqueous environments. Cholesterol H O بیو سنتز کلسترول - بیو سنتز statin drugs&Cholesterol کلسترول دفع کلسترول cholesterol. متابولیسم پروتئین ها و اسیدهای امینه Dietary protein Pepsin Polypeptide Mixture Trypsin, Chymotrypsin carboxypeptid ase Aminopeptidase Tripeptidase dipeptidase Non Protein Nitrogen (NPN) انواع پروتئین های بافتی سنتز تجزیه Aminoacid Deamination Aminoacid & oligopepti Blood Aminoacid R-CH-COOH NH2 Liver NH3 Urea کتو اسید Kidney ATP سیکل کربس NH4 Urine متابولیسم اسیدهای آمینه اسیدهای امینه ازسه طریق وارد چرخه متابولیسم میشوند: -1ازطریق غذا -2 .ازطریق انحالل پروتئینها -3 .سنتز در بدن واکنشهای اسید های آمینه: -1واکنشهای عمومی شامل دآمینه و دکربوکسیله. – 2سرنوشت عامل آمین. – 3سرنوشت ریشه کربنی اسید آمینه. دآمینه شدنDeamination 1-Transaminases: I(AST) aspartate aminotransferase Serum Glutamate:oxaloacetate transaminase [SGOT] COO COO COO CH2 COO CH2 CH2 CH2 CH2 CH2 HC NH3+ + COO C O COOPyridoxal phosphate (PLP)- C O + COO HC NH3+ COO aspartate -ketoglutarate oxaloacetate glutamate Aminotransferase (Transaminase) II-Serum Glutamate:pyruvate transaminase [SGPT] alanine aminotransferase (ALT) CH3 HC COO COO CH2 CH2 CH2 NH3+ COO + C CH3 O COO phosphate Pyridoxal C CH2 O COO + HC NH3+ COO (PLP)- alanine -ketoglutarate pyruvate glutamate Aminotransferase (Transaminase) دآمینه شدنDeamination 2-Glutamate dehydrogenase [GluDH] دآمینه شدنDeamination 3- L –amioacid oxidase : R-CH –COOH NH2 H2O R-CO-COOH NH3 دآمینه شدنDeamination Non Oxidativ Deamination دآمینه شدن غیر اکسیاتیو glutaminase glutamine + H2O glutamate + NH3 Aspargine +H20 Asparginase Asparticacid + NH3 Serine Dehydratase catalyzes: serine pyruvate + NH3 سرنوشت عامل آمین . سرنوشت ریشه کربنی اسید های امینه ای که ریشه کربنی آنها تبدیل به اسید پیرویک یا یکی از واسطه های سیکل کربس شود به آنها اسید های امینه گلیکوژنیک یا قند ساز میگویند. اسید های امینه ای که ریشه کربنی آنها تبدیل به استیل کوا یا استواستیل کوا شود به آنها اسید های امینه کتوژنیک یاستون ساز میگویند. Glucose Phosphoenolpyruvate Glycine Cysteine Serine Alanine Threonine Tryptophan Isoleucine Leucine Leucine Lysine Phenylalanine Tyrosine Tryptophan Pyruvate Asparagine Aspartate Tyrosine Phenylalanine Isoleucine Valine Methionine Threonine Acetyl CoA Acetoacetyl CoA Oxaloacetate Fumarate Succinyl CoA Citrate -ketoglutarate Glutamate Glutamine Histidine Proline Arginine Fates of the carbon skeletons of amino acids. Glucogenic amino acids are shaded red, ketogenic amino acids are shaded green and glucoketogenic 32 amino acids are shaded blue. Histidine Metabolism: Histamine Formation H N + NH 3 CH 2CHCO 2- Histidine decarboxylase H N CH 2CH 2NH 2 N Histidine CO2 N Histamine Histamine: • Synthesized in and released by mast cells • Mediator of allergic response: vasodilation, bronchoconstriction (H1 receptors) • H1 blockers: Diphenhydramine (Benadryl) Loratidine (Claritin) • Stimulates secretion of gastric acid (H2 receptors) • H2 blockers: Cimetidine (Tagamet); ranitidine (Zantac) HO HO متابولیسم فنیل آالنین و تیروزین فنیل کتون ها سنتز انواع پروتئینها بافتی NH 3+ Phenylalanine (Essential) CH 2CHCO 2- (Phenylalanine Phenylketonuria (PKU) Disease سنتز انواع پروتئینها بافتی hydroxylase) HO Tyrosine NH 3+ NH 3 + DOPA CH 2 CHCO 2 CH 2CHCO 2 - - ید+ T3& T4 Tyrosine Tyrosinase NADPH + H+ Albinism Epinephrine (Adrenaline) تیروئید Melanine )الکاپتونHomogentisate Alkaptonuria × Norepinephrine Homogentisate dioxygenase Fumarate + acetoacetate ATP سیکل کربس Catecholamine Biosynthesis HO HO NH 3 Tyr hydroxylase + NH 3+ CH 2CHCO 2 - O2 HO CH 2CHCO 2 - HO Tyrosine HO Catechol Dihydroxyphenylalanine (DOPA) DOPA decarboxylase Epinephrine (Adrenaline) CHCH 2NHCH 3 OH Methyl transferase S-Adenosylhomocysteine Dopamine hydroxylase HO CH 2CH 2NH 2 HO HO CO2 Dopamine SAM HO DOPA, dopamine, norepinephrine, and epinephrine are all neurotransmitters CHCH 2NH 2 OH Norepinephrine 35 L-DOPA in Parkinsonism Blood Brain L-DOPA L-DOPA Dopamine HO CH 3 HO Blocks CH 2 -C-CO 2 H Carbidopa NHNH 2 Dopamine Blood Parkinsonism associated with dopamine in brain through loss of neurons in basal ganglia. Carbidopa + L-DOPA Brain Barrier 36 Monoamine Oxidase (MAO) HO HO MAO (in mitochondria) CHCH 2NHR' HO HO R R R’ OH H Norepi OH CH3 Epi H H Dopamine R Aldehyde dehydrogenase HO HO MAO inhibitors (e.g., tranylcypromine) are useful in the treatment of depression Brain levels of dopamine and norepi.; also serotonin CHCHO CHCO 2H Urinary R metabolite R=OH Vanillylmandelic acid (VMA) R=H Homovanillic acid (HVA) 37 Tyramine OH MAO CH 2 CH 2 NH 2 OH CH 2CHO Tyramine ( blood pressure) • Tyramine found naturally in several types of cheese; also beer and red wine. • Tyramine intake can cause hypertensive crisis in persons taking a MAO inhibitor ( norepi release) 38 Catechol-O-Methyl Transferase (COMT) HO HO HO COMT CHCH 2NHR' Active catecholamine R CHCH 2 NHR' CH 3 O SAM S-Adenosylhomocysteine R Inactive metabolite • COMT found in cytoplasm • Terminates activity of catecholamines • Catecholamine excretion products result from combined actions of MAO and COMT • Inhibitors of COMT (e.g., tolcapone) useful in Parkinson’s disease 39 Melanin Formation HO Tyr hydroxylase NH 3+ CH 2CHCO 2 - HO NH 3+ O2 Tyrosine CH 2CHCO 2 - HO DOPA Tyrosinase O Melanin (Black polymer) Highly colored polymeric intermediates O Melanin formed in skin (melanocytes), eyes, and hair In skin, protects against sunlight Albinism: genetic deficiency of tyrosinase CH 2CHCO 2+ NH 3 Dopaquinone 40 + NH 3 Indole ring + NH 3 CH 2 CHCO 2 - Trp hydroxylase HO CH 2 CH 2 NH 2 CH 2 CHCO 2 - HO Decarboxylase N H O2 5-Hydroxytryptophan Tryptophan (Trp) N H N H CO2 MAO 5-Hydroxytryptamine (5-HT); Serotonin CH 2CHO HO N H Dehydrogenase CH 2 CO 2H CO 2H B3 HO N H N 5-Hydroxyindole acetic acid (5-HIAA) (Urine) Amino Acids Formed From Ketoglutarate O O 2 CCH 2 CH 2 CCO -Ketoglutarate 2 - 4 Steps Transamination or Glutamate dehydrogenase CO 2- + N NH3+ - O 2 CCH 2 CH 2 CHCO 2 - Glutamate Glutamine synthase O H 5 Steps Glutamine Proline NH3+ + H3 NCH 2 CH 2 CH 2 CHCO 2 - Ornithine Urea Cycle NH3+ H2 NCCH 2 CH2 CHCO 2 - H NH 2 NH 3+ + H2 N=C-HN CH 2 CH 2 CH 2 CHCO Guanidino group 2 - 42 Arginine Synthesis of Nitric Oxide NH 2 NH 3+ + H2 N=C-HN CH 2 CH 2 CH 2 CHCO Arginine 2 - Nitric oxide synthase (NOS) NH 3+ NH 2 CONH CH 2 CH 2 CH 2 CHCO 2 - + NO Citrulline 43 Nitric Oxide • Cell messenger • Implicated in a wide range of physiological and pathophysiological events: • Vasodilation: • Activates guanylyl cyclase cGMP • Nitroglycerin Glycerin + NO • Sildenafil (Viagra): in vascular smooth muscle: NO Blocks cGMP Phosphodiesterase-5 GMP 44 Formation of Serine CO 2 - Glucose Glycolysis Dehydrogenase H C OH NAD+ CH 2 OPO 3-2 3 Steps NADH + H+ 3-Phosphoglycerate Pyruvate C=O CH 2 OPO 3-2 3-Phosphohydroxypyruvate Inhibits CO 2 CO 2 - Glutamate Transaminase -Ketoglutarate - CO 2 - Phosphatase H C NH 3 + CH 2 OH Serine (Ser) H C NH 3 + CH 2 OPO 3-2 3-Phosphoserine 45 Conversion of Serine to Glycine H Dihydrofolate reductase Folate H2 N N N CO 2 - N N OH CH2 NHR H C NH 3 + H Tetrahydrofolate (FH4) CH 2 OH Serine hydroxymethyl transferase (PLP-dep.) H N Key intermediate in biosynthesis of purines and formation of thymine Serine CO 2 N Glycine CH2 H C NH 3 + N H H2C N5, N10-Methylene FH4 Important in biosynthesis of heme, porphyrins, and purines 46 Sulfur-Containing Amino Acids NH 3 Methionine Synthase (Vit. B12-dep.) + CH 3SCH 2CH 2CHCO Methionine (Essential) - + FH4 2 NH 3+ HS CH 2CH 2CHCO 2 + 5-Methyl L-Homocysteine CO 2 - Cystathionine b-synthase (PLP-dep.) NH 3+ OH - CH 3CHCH 2CO 2 b-Hydroxybutyrate FH4 Cystathionine lyase + HS CH 2CHCO 2Cysteine (Non-essential) H C NH 3 + Serine CH 2 OH NH 3+ - SCH 2CH 2CHCO 2 CH 2CHCO 2NH 3 + Cystathionine 47 Homocysteine Homocysteinuria • Rare; deficiency of cystathionine b-synthase • Dislocated optical lenses • Mental retardation • Osteoporosis • Cardiovascular disease death High blood levels of homocysteine associated with cardiovascular disease • May be related to dietary folate deficiency • Folate enhances conversion of homocysteine to methionine 48 Methionine Metabolism: Methyl Donation NH 2 N N NH 3+ CH 3SCH 2CH 2CHCO 2 S-Adenosyl methionine synthase -O + 2 CCHCH 2 CH 2 -S-H2 C NH 3 + ATP Methionine N + H3 NCH 2 CH 2CH 2-S-H 2C + CO2 CH 3 OH OH N N -O O S-Adenosyl Methionine (SAM) N N N N CH 3 NH 2 NH 2 N O OH OH SAM Decarboxylase Decarboxylated SAM N N 2 CCHCH 2 CH 2 -S-H2 C O Methyltransferases R-CH3 NH 3 + S-Adenosyl homocysteine R-H OH OH 49 Polyamines • Spermidine and spermine found in virtually all procaryotic and eucaryotic cells • Precise role undefined • Bind to nucleic acids • Inhibition of biosynthetic pathway: CO 2H NH 2 H2N CHF 2 -Difluoromethylornithine (DFMO) (Eflornithine) - inhibits ODC; used to treat Pneumocystis carinii infectons 50 Polyamine Biosynthesis NH3+ + H3 NCH 2 CH 2 CH 2 CHCO 2 Ornithine (from urea cycle) Ornithine decarboxylase (ODC) (PLP-dep.) + H3N Putrescine CO2 Decarboxylated SAM Spermidine synthase H + H3N N+ + N H H + NH 3 + NH 3 Spermine synthase H Spermine 5’-Methylthioadenosine Decarboxylated SAM + H3N 5’-Methylthioadenosine H +N H + NH 3 Spermidine 51 Creatine and Creatinine NH 2 Arginine-glycine transamidinase (Kidney) + NH 3 + H2 N=C-HN CH 2 CH 2 CH 2 CHCO 2 NH 2 + H2 N=C-HN CH 2 CO 2 - - Glycine Arginine Ornithine Guanidoacetate SAM + ATP H N Creatinine HN (Urine) O Guanidoacetate Methyltransferase (Liver) Non-enzymatic (Muscle) N CH 3 NH 2 Creatine Creatine kinase (Muscle) + H2 N=C-N CH 2 CO 2 CH 3 ATP ADP + Pi S-Adenosylhomocysteine + ADP NHPO 3-2 + H2 N=C-N CH 2 CO 2 CH 3 Phosphocreatine 52 Creatine and Creatinine Creatine: • Dietary supplement • Used to improve athletic performance Creatinine: • Urinary excretion generally constant; proportional to muscle mass Creatinine Clearance Test: • Compares the level of creatinine in urine (24 hrs.) with the creatinine level in the blood • Used to assess kidney function • Important determinant in dosing of several drugs in patients with impaired renal function 53 ساختمان نوکلئوتید ها و اسیدهای نوکلئیک ساختمان نوکلئوتید ها و اسیدهای نوکلئیک Nucleic Acid Structure A. B. C. D. E. F. G. Structure of nucleotides Nitrogenous bases Pentose sugars Nucleosides Nucleotides Nucleotide chains Structure of B-DNA A. Structure of Nucleotides • A nucleotide is composed of A nitrogenous base:Purines:Adenine& Guanine Pyrimidines:Cytosine &Thymine&Uracil A pentose sugar A phosphate group Nucleosides & Nucleotides • • Base + sugar nucleoside Base + sugar + phosphate(s) nucleotide • Nucleoside A pentose sugar molecule with a nitrogenous base attached to the 1´ carbon Nucleosides are named by using the root of the base name, plus the suffix “-osine” (for purines) or “-idine” (for pyrimidines) Nucleosides with deoxyribose sugars are designated with the prefix “deoxy-” NUCLEIC ACID STRUCTURE • DNA and RNA are large macromolecules with several levels of complexity • Nucleotides form the repeating units • Phosphodiester bonds link nucleotides to form a strand • Two strands interact to form a double helix • The double helix interacts with proteins resulting in 3-D structures in the form of chromatin 3D structure Nucleotide Polymerization Reaction: Phosphodiester Bond Formation Figure 9.11 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 9-30 Base Pairing Key to DNA Structure Features of the DNA Double Helix 2 nm 5end 3end H H HH H P One complete turn 3.4 nm A S S P P S G C P S P 5phosphate S G C P S SC P S P S P S P S A T S P G C S P S P C G S S P T A P S P S P 3hydroxyl P S G P S C G P S P T A S P S G C S P One nucleotide A T S 0.34 nm S P S P P SC G S P S C G P N O N O– H N O P O CH2 O O– HH HH N O H HH N H O O N O O P O CH2 O N NH2 O– HH HH H H H H N N H2N N N O H O N O P O CH2 O N O O– HH HH H CH3 OH H 3end O– CH2 O P O O H NH22 N NH N H HH O N H2N HO HH O H O– CH2 O P O O H HH N N HH O H O– CH2 O P O O– H2N 5 end Features of the DNA Double Helix Minor groove Major groove Minor groove Major groove Ball-and-stick model of DNA Space-filling model of DNA انواعDNA BDNA : هلیکس آن راست گرد می باشد. در هر دور آن 10جفت باز وجود دارد. طول هر دور آن 4/3Åمی باشد. فاصله دو رشته آن )2 nm ( 20Åاست. بازها نسبت به محور هلیکس بصورت عمود قرار می گیرند. در ساختمان آن 2نوع شیار دیده می شود: major grove - minor grove طول شیار بزرگ )2/2 nm ( 22Å : طول شیار کوچک )2/1 nm ( 12Å : انواعDNA در صورت کم بودن رطوبت محیط یا زیاد بودن نمک محیط ZDNAو ADNAبوجود می آیند. :ADNA هلیکس آن راست گرد می باشد. در هر دور آن 11جفت باز وجود دارد. بازها نسبت به محور هلیکس زاویه 23درجه دارند. در ساختمان آن فقط یک نوع شیار دیده می شود. :ZDNA هلیکس آن چپ گرد می باشد. در هر دور آن 12جفت باز وجود دارد. بازها نسبت به محور هلیکس زاویه 180درجه دارند. در ساختمان آن فقط یک نوع شیار دیده می شود. BDNA ADNA Comparison of A, B, and Z forms of DNA RNA Structure • The primary structure of an RNA strand is much like that of a DNA strand • RNA is made as a single strand only, however it may form a double stranded structures • RNA strands can be a 10s to1000s of nt in length • RNA is made from a DNA template - only one of the two strands of a DNA helix is used as the template • RNA contains uracil rather than thymine Messenger RNA=mRNA Transfer RNA=tRNA Ribosomal RNA=rRNA 9-57 Figure 9.22 9-58 Messenger RNAs • Contain protein coding information ATG start codon to UAA, UAG, UGA Stop Codon A cistron is the unit of RNA that encodes one polypeptide chain • Base pairing/3D structure is the exception Can be used to regulate RNA stability termination, RNA editng, RNA splicing Transfer RNA (tRNA) • Is a single strand folded into a cloverleaf shape • Has a specific site to which specific amino acids can attach • There is a different type of tRNA for each type of amino acid • Each type of tRNA has three bases which are specific to the type of amino acid which will attach • These three bases are called the anticodon tRNA Specific amino acid attaches More simply drawn Anticodon – specific to the amino acid which attaches to this tRNA molecule متابولیسم اسیدهای نوکلئیک Degradation of nucleic acid Nucleoprotein In stomach Gastric acid and pepsin Nucleic acid Protein In small intestine Endonucleases: RNase and DNase Nucleotide Nucleotidase Phosphate Nucleoside Nucleosidase Base Ribose Significances of nucleotides 1. Precursors for DNA and RNA synthesis 2. Essential carriers of chemical energy, especially ATP 3. Components of the cofactors NAD+, FAD, and coenzyme A 4. Formation of activated intermediates such as UDP-glucose and CDP-diacylglycerol. 5. cAMP and cGMP, are also cellular second messengers. There are two pathways leading to nucleotides • De novo synthesis: The synthesis of nucleotides begins with their metabolic precursors: amino acids, ribose-5-phosphate, CO2, and one-carbon units. • Salvage pathways: The synthesis of nucleotide by recycle the free bases or nucleosides released from nucleic acid breakdown. § 2.1 De novo synthesis • Site: in cytosol of liver, small intestine and thymus • Characteristics: a. Purines are synthesized using 5phosphoribose(R-5-P) as the starting material step by step. b. PRPP(5-phosphoribosyl-1-pyrophosphate) is active donor of R-5-P. c. AMP and GMP are synthesized further at the base of IMP(Inosine-5'-Monophosphate). Purine Nucleotide Synthesis Purine Nucleotide Synthesis 2- O3P O CH2 H O H H H OH OH OH -D-Ribose-5-Phosphate (R5P) ATP Ribose Phosphate Pyrophosphokinase AMP 2- O3P O CH2 O H H H H O O P O O P O OH OH O O 5-Phosphoribosyl--pyrophosphate (PRPP) Glutamine + H2O Amidophosphoribosyl O C Transferase HN Glutamate + PPi 2- O3P O CH2 H b H H H OH HC NH2 O OH b-5-Phosphoribosylamine (PRA) C C N 4 CH 5 N N 2- O3P O CH2 H H OH O H H OH Inosine Monophosphate (IMP) P P O CH2 O Bas e ribonucleotide reductase Mg 2+ OH OH P P O CH2 O H 2O thioredoxin S S SH thioredoxin NDP SH £¨ N=A, G, C, U£© FAD + NADP thioredoxin reductase NADPH + H OH Bas e H dNDP ATP + kinase ADP dNTP Deoxyribonucleotide synthesis at the NDP level Purine nucleotide biosynthesis is regulated by feedback inhibition Purine Salvage Pathway . adenine phosphoribosyl transferase Adenine PRPP AMP PPi O N O N 2-O N N N Hypoxanthine O N N hypoxanthine-guanine phosphoribosyl transferase (HGPRT) PRPP N N Guanine NH2 3POH2C O N N N HO OH IMP O PPi N 2-O 3POH2C O N N N NH2 HO OH GMP . Absence of activity of HGPRT leads to Lesch-Nyhan syndrome. تجزیه و دفع بازهای پورین - Gout Impaired excretion or overproduction of uric acid Uric acid crystals precipitate into joints (Gouty Arthritis), kidneys, ureters (stones) Lead impairs uric acid excretion – lead poisoning from pewter drinking goblets Fall of Roman Empire? Xanthine oxidase inhibitors inhibit production of uric acid, and treat gout Allopurinol treatment – hypoxanthine analog that binds to Xanthine Oxidase to decrease uric acid production The uric acid and the gout Out of body In urine Diabetese nephrosis …… Hypoxanthine Xanthine Uric acid Over 8mg/dl, in the plasma Gout, Urate crystallization in joints, soft tissue, cartilage and kidney ALLOPURINOL IS A XANTHINE OXIDASE INHIBITOR A SUBSTRATE ANALOG IS CONVERTED TO AN INHIBITOR, IN THIS CASE A “SUICIDE-INHIBITOR” Element source of pyrimidine base C Gl n N3 4 C 5 As p C O2 C 2 1 N 6C synthesis of carbamoyl phosphate •Carbamoyl phosphate synthetase(CPS) exists in 2 types: •CPS-I, a mitochondrial enzyme, is dedicated to the urea cycle and arginine biosynthesis. •CPS-II, a cytosolic enzyme, used here. It is the committed step in animals. 2 ATP + 2 ADP + Glutamate + Pi HCO3 + Glutamine + H2O Carbamoyl Phosphate Synthetase II Pyrimidine Synthesis NH2 O TMP C PO3-2 O CMP Carbamoyl Phosphate Aspartate Aspartate HO Transcarbamoylase (ATCase) 2 Pi O Dihydroorotase C O C C O PRPP PPi 2- O3P O CH2 H C N H Orotate CH C CH N O CH HN HN O H COO Orotate Phosphoribosyl Transferase b H H OH OH Uridine Monophosphate (UMP) Synthesis of UMP from carbamoyl phosphate 5. Regulation of de novo synthesis ATP + CO2 + Gln carbamoyl phosphate purine nucleotide carbamoyl aspartate PRPP ATP + R-5-P UM P pyrimidine nucleotide UTP CTP تجزیه ودفع بازهای پیریمیدین Thymidine Cytosine Uracil γ aminoisobutyrate γ aminoisobutyrate CO2+NH3 β alanine +CO2+NH3 Succinyl COA Pyrimidine Catabolism enzyme specification.
