Amino Acid Degradation The Carbon Skeletons

OUTLINE: Protein Degradation (Catabolism) Introduction and review Transport Glycogenolysis Glycolysis Other sugars Pasteur: Anaerobic vs Aerobic Digestion Inside of cells Protein turnover Ubiquitin Proteosome Exam-1 material Fermentations Pyruvate Krebs’ Cycle Oxidative Phosphorylation Exam-2 material Ammonia free transamination ß know mechanism Carbamoyl-phosphate synthetase Urea Cycle 4 Steps Electron transport Chemiosmotic theory: Phosphorylation Fat Catabolism Exam-3 material diet storage Fatty acid Catabolism FOUR stages in the catabolism of lipids: Mobilization from tissues (mostly adipose) hormone regulated specific lipases glycerol Activation of fatty acids Fatty-acyl CoA Synthetase Transport carnitine Oxidation Rationale Saturated FA b-oxidation 4 steps: dehydrogenation hydration oxidation thiolase OUTLINE: Amino-Acid Degradation Dealing with the nitrogen Ornithine transcarbamylase Arginino-succinate synthetase Arginino-succinase Arginase Energetics Urea Bi-cycle Dealing with the carbon Fates of the 29 nitrogen atoms in 20 AA: 9 ammonia 18 transamination 2 urea Seven Families 1. ADENQ (Transaminase/deaminase Family) 2. RPH (Glu Family) Oxidase One-carbon (1-C) metabolism THF SAM 3. GSC (Pyruvate Family) PLP uses 4. MT – 1-C metabolism (a-Ketobutyrate Family) 5. FY – oxidases (Aromatic Family) 6. KW (a-Ketoadipate Family) 7. VIL (Branched-chain AA Family (BCAA)) Convergence with Fatty acid-odd chain Nucleic Acid and Nucleotide Degradation energetics Unsaturated FA energetics Odd-chain FA Ketone Bodies Other organelles Nucleic Acids Nucleotides Salvage pathway Degradation of purines Degradation of pyrimidines Connection of sugar metabolism Amino Acid Degradation: the carbon “skeletons” A. Concepts 1. Convergent 2. ketogenic/glucogenic The SEVEN 3. Reactions seen before B. Transaminase (A,D,E) / Deaminase (Q,N) Family C. Related to biosynthesis (R,P,H; C,G,S; M,T) 1. Glu Family a. b. (7) Families Introduce oxidases/oxygenases Introduce one-carbon metabolism (1C) 2. Pyruvate Family a. PLP reactions a. 1-C metabolism 3. a-Ketobutyric Family (M,T) D. Dedicated 1. Aromatic Family (F,Y) a. oxidases/oxygenases 2. a-Ketoadipic Family (K,W) 3. Branched-chain Family (V,I,L) E. Convergence with Fatty Acids: propionyl-CoA 29 N 1 V,I,L Amino Acid Degradation • Degradation of branched-chain amino acids does not occur only in the liver • Leucine, isoleucine, and valine are oxidized for fuel in muscle, adipose tissue, the kidneys, and the brain • Branched-chain amino acids are degraded to succinyl-CoA, an important citric acid cycle intermediate, and acetyl-CoA, an important fuel molecule 7 st eps CO2 3 steps 5 steps Ketone Bodies HMG-CoA 6 Isoprene biosynthesis CO2 5 4 3 2 1 b-Hydroxy-methyl-glutaryl-CoA (OMSGAP) Amino Acid Degradation Alanine Cysteine Glycine Serine Pyruvate Glutamate Glutamine Histidine Proline Arginine Methionine Threonine a-Ketoglutarate OXIDATIVE DECARBOXYLATION V,I,L Acetyl-CoA pyruvate dehydrogenase com plex Dehydrogenase (FAD) Hydratase (H2 O) Succinyl-CoA a -ketoglutarate dehydrogenase com plex Dehydrogenase (NAD+ ) Thiolase (CoASH) a-Ketobutyrate Propionyl-CoA 2 Hydrolase (CoASH) 2 Carboxylase (biotin) a-Ketoadipate Glutaryl-CoA 2 2 2 Crotonyl-CoA 2Acetyl-CoA Crotonyl-CoA | – CO O 2 | – CO O biotin Glutaconcyl-CoA CO2 CoASH a-Ketoisovalerate Methyl malonyl-CoA || O OH a-Keto b-methylvalerate PLP a-Keto isocaproate CoASH Isobutryl-CoA TPP FAD Lipoic acid a-Methybutryl-CoA OH Branched-chain a-keto acid dehydrogenase complex || O Lysine Tryptophan a-methylacetoacetyl-CoA CO2 Acetyl-CoA + Propionyl-CoA Isovaleryl-CoA CH2 OH Biotin HMG-CoA 2 V,I,L Amino Acid Degradation • • • Intermediates of the central metabolic pathway Some amino acids result in more than one intermediate. Ketogenic amino acids can be converted to ketone bodies. Seven to Acetyl-CoA • Leu,7 Ile,7 Thr, Lys,6 Trp,6 Phe,5 Tyr5 Glucogenic amino acids can be converted to glucose. Six to pyruvate3,1 Ala, Cys, Gly, Ser, Thr, Trp Five to a-ketoglutarate2,1 Arg, Glu, Gln, His, Pro Four to succinyl-CoA7,4 Ile, Met, Thr, Val Two to fumarate Phe, Tyr 5 Two to oxaloacetate1 [F,Y] [K,W] a-ketoadipic a-ketobutyric Asp, Asn ✓1Trans-/de-aminase family ✓2Glu family ✓3Pyruvate family ✓4Alpha-keto butyric family ✓5Aromatic family ✓6Alpha-keto adipic family ✓7Branched-chain family propionylCoA Amino Acid Degradation Meets Fatty Acid Degradation Oxidation of Propionyl-CoA Threonine Valine thymidines Odd-Chain Fatty Acids Biotin L– Vitamin B12 (R) (R) 3 Amino Acid Degradation Meets Fatty Acid Degradation Only a handful of enzymes require Coenzyme B12 Diet Vitamin B (cobalamin) (OH-Cbl) 12 Saliva Plasma IF-1 (OH-Cbl) Stomach TC-1 (OH-Cbl) H2O (Co3+) Amino Acid Degradation Meets Fatty Acid Degradation Complex Cobalt-Containing Compound: Coenzyme B12 Nobel Prize 1957 1964 4 Amino Acid Degradation Meets Fatty Acid Degradation The Vitamin B12 Story Amino Acid Degradation Meets Fatty Acid Degradation 5 Amino Acid Degradation: Overview Fates of the 29 nitrogen atoms in the 20 amino acids: [★] 9 ammonia [◉] 17 transaminase (mostly Glu) [⧆] 1 reductive deamination (also Glu) [❊] 2 urea Glutamine ★ Histidine 4 Steps ★ Proline ★ THF Arginine 2 Steps❊❊ 2 Steps Glu-semialdehyde ◉ ◉◉◉◉◉ Leucine ◉ 2 Steps ps 3 Ste Isoleucine HMG-CoA 5 Steps glutaryl-CoA Lysine 4 Steps ⧆ ◉ Valine 5 Steps SAM 2 Steps 2 Steps cycle 4S ps tep Ste 5 s ★ 3 Steps a-ketobutyric Propionyl-CoA ◉ Methionine ◉ ★ Threonine ◉ ◉ 5/6 Steps Cysteine a-ketoadipic ◉ 3 Steps ★ 5 Steps 3 Steps Tryptophan ◉ ◉ Alanine THF cycle ★ ◉◉ Serine 1.Transaminase/Deaminase Family 2.Glu Family 3.Pyruvate Family 4.a-ketobutyric Family 5.Aromatic Family 6.a-ketoadipic Family 7.Branched-chain Family Glycine ★ CO2 + NH4 + ★ Asparagine Oxidative decarboxylation by a complex yielding NADH -transaminase (Asp) -reductive deamination (Glu/Arg) -deaminase (ammonia) -urea 6 Amino Acid Degradation: Overview TABLE 18-2 Some Human Genetic Disorders Affecting Amino Acid Catabolism Medical condition Approximate incidence (per 100,000 births) Defective process Defective enzyme Symptoms and effects Albinism <3 Melanin synthesis from tyrosine Tyrosine 3monooxygenase (tyrosinase) Lack of pigmentation; white hair, pink skin Alkaptonuria <0.4 Tyrosine degradation Homogentisate 1,2dioxygenase Dark pigment in urine; late-developing arthritis Argininemia <0.5 Urea synthesis Arginase Mental retardation Argininosuccinic acidemia <1.5 Urea synthesis Argininosuccinase Vomiting; convulsions Carbamoyl phosphate synthetase I deficiency <0.5 Urea synthesis Carbamoyl phosphate synthetase I Lethargy; convulsions; early death Homocystinuria <0.5 Methionine degradation Cystathionine βsynthase Faulty bone development; mental retardation Maple syrup urine disease (branchedchain ketoaciduria) <0.4 Isoleucine, leucine, and valine degradation Branched-chain α-keto acid dehydrogenase complex Vomiting; convulsions; mental retardation; early death Methylmalonic acidemia <0.5 Conversion of propionyl-CoA to succinyl-CoA Methylmalonyl-CoA mutase Vomiting; convulsions; mental retardation; early death Phenylketonuria <8 Conversion of phenylalanine to tyrosine Phenylalanine hydroxylase Neonatal vomiting; mental retardation Amino Acid Degradation: Overview We learned that: • amino acids from protein are an important energy source in carnivorous animals • the first step of AA catabolism is transfer of the NH3 via PLP-dependent aminotransferase usually to a-ketoglutarate to yield L-glutamate • in most mammals, toxic ammonia is quickly recaptured into carbamoyl phosphate and passed into the urea cycle • amino acids are degraded to pyruvate, acetyl-CoA, αketoglutarate, succinyl-CoA, and/or oxaloacetate • amino acids yielding acetyl-CoA are ketogenic • amino acids yielding other end products are glucogenic • genetic defects in amino-acid degradation pathways result in a number of human diseases • amino acid catabolism is dependent on a variety of cofactors, including THF, ado-Met (SAM), Cbl, biotin, and PLP 7 Nucleotide Degradation Nucleotide Degradation The Digestion Pathway nucleases & phosphodiesterases Duodenum Non-specific phosphatases nucleosides) • Ingestion of food always includes nucleic acids. • As you know from BI 421, the low pH of the stomach does not affect the polymer. • In the duodenum, zymogens are converted to nucleases and the nucleotides are converted to nucleosides by non-specific phosphatases or nucleotidases. • Only the non-ionic nucleosides are taken up in the villi of the small intestine. • In the cell, the first step is the release of the ribose sugar, most effectively done by a non-specific nucleoside phosphorylase to give ribose 1-phosphate (Rib1P) and the free bases. • Most ingested nucleic acids are degraded to Rib1P, purines, and pyrimidines. 8 Nucleotide Degradation: Overview Fate of Nucleic Acids: Once broken down to the nitrogenous bases they are either: Nucleotides Pi Purine Nucleoside Phosphorylase Nucleosides Pi aD-Rib 1-P & aD-dRib 1-P Bases Purine & Pyrimidine Salvage Pathway The Salvage Pathways are in competition with the de novo biosynthetic pathways, and are both ANABOLISM 1. Salvaged for recycling into new nucleic acids (most cells; from internal, not ingested, nucleic acids). 2. Oxidized (primarily in the intestine and liver) by first converting to nucleosides, then to Oxidation –Uric Acid (purines) –Acetyl-CoA & succinyl-CoA (pyrimidines) 9