Dr. M. Sasvari METABOLISM OF AMINO ACIDS 2. The fate of the carbon sceleton 3 N + C R
Active C 1 intermediers The folate derivatives
structure s Folate (F) - vitamin Folate, 2 F, 4 F Dihydrofolate ( 2 F) Tetrahydrofolate ( 4 F) DFR ( 2 F reductase) NADP NADP + Folate deficiency: similar to B12 deficiency (megaloblastic anemia), CNS problems Normal diet contains sufficient folate Pregnancy: early folate administration decreases the chance for spina bifida (?)
pathway 5 10 N N C N 2 + N 5 -formimino- 4 F is N 4 + 4 F derivatives 5 10 N N 4 F 5 10 N N 2 O + C N 5 -N 10 -methenyl- 4 F Trp 5 10 N N C O N 10 -formyl- 4 F nucleotides Ser NADP NADP + 5 10 N N Gly blood C 2 N 5 -N 10 -methylene- 4 F NAD NAD + 5 10 N N C 3 N 5 -methyl- 4 F C 2-4 F C 3-4 F dtmp MTFR (methylene 4 F reductase) SAM cycle
The folate cycle is Trp Gly Ser DFR 2 F 4 F omocys C 2-4 F dtmp C 3-4 F Met
Active C 1 intermediates The SAM cycle
Key structure s Cysteine (Cys), 3C omocysteine, 4C omocys Methionine (Met), 5C C 3 thiol S thioether S thiol S C 2 C 2 C 2 C 2 C 2 3 N + a C 3 N + a C O a C Serine (Ser), 3C O omoserine, 4C omoser O
The SAM cycle 4 F omocys S SA hydrolase SA adenosine S-adenosyl-omoCys + S adenosyl omocys methyltransferase Prosthetic group: Methyl-B12 C 3-4 F C 3 S Met Met adenosyl transferase ~ C 3 SAM - dependent methylases SAM S-adenosyl-Met ATP PPi + Pi C 3 + S activated methyl group adenosyl
4 F omocys adenosine SA 4 F cycle B12 SAM cycle ~C 3 C 2-4 F C 3-4 F Met SAM dump dtmp purine synthesis Cell division Folate or B12 deficiency: 1. igh adenosine and homocys in the blood 2. Methyl trap (high C 3-4 F, low C 2-4 F) Inhibition of cell division
Synthesis of Cys from Ser and Met Ser O C 2 3 N + a C S C 2 C 2 Cys S 3 N + a C Cystathione synthase (PLP vitb 6 ) Cystathionine - 2 O + 2 O S omocys Met SAM cycle SA SAM -N 3 Cystathionine synthase deficiency yperhomocysteinemia? atherosclerosis aketobutyrate O C 3 C 2 a C
Thr * Succinyl-CoA forming amino acids (essential amino acids) Bile acid synthesis Val Ile acetylcoa a-ketobutyrate Propionyl CoA Methylmalonyl-CoA B12 CAC Succinyl-CoA Cys Cystathionine Ser omocys SA food Met SAM * Thr dehydratase (see before)
Bile acids synthesis Thr * Val Ile acetylcoa a-ketobutirate a-ketobutyrate Propionyl CoA Methylmalonil Methylmalonyl-CoA B12 CAC Succinyl -CoA NAD + NAD ATP ADP+P i S-CoA S-CoA S-CoA C O a C O 1. C O 2. C O 3. 4. C 2 C 2 CO 2 C 2 CO 2 C COO C 2 C 3 C 3 1. a-ketobutyrate dehydrogenase complex 2. propionylcoa carboxylase (biotin) 3. methylmalonylcoa racemase (D L) 4. methylmalonylcoa mutase (5 adenosyl-cobalamine) C 3 Methylmalonic aciduria: - deficiency of (adenosyl)b12 - deficiency of mutase
Glucogenic (glucoplastic) and ketogenic (ketoplastic) amino acids glucose pyruvate Acyl-CoA fumarate OXA succinylcoa CAC akg Acetyl-CoA Ile acetoacetate b-oxidation Val, Ile Thr, Met Lys, Leu, Tyr ( Phe), Trp ketone bodies
Catabolism of branched chain amino acids Val, Leu, Ile (essential amino acids) Val (C5) Leu (C6) Ile (C6) Branched chain amino acid transaminase a-keto-isovalerate a-keto-isocapronate a-keto-b-methyl-glutarate Branched chain a-ketoacid dehydrogenase (BCKD) (similar reaction mechanism and coenzyme need to pyruvate dehydrogenase) Similar reactions to b oxidation Isobutiryl- CoA Isovaleryl- CoA a-methyl-butiryl-coa (NAD, FAD 2 production) Propionyl CoA MG CoA Acetyl CoA Propionyl CoA Acetyl CoA acetoacetate Maple syrup urine disease Deficiency of BCKD (ketoacidosis, mental retardation)
Oxalacetate forming amino acids: Asp and Asn Synthesis of these non-essential amino acids Asp Catabolism + Synthesis: Transamination by ASAT (see before) reversible Role: Amino group donor (fumarate remains) - urea cycle: arginosuccinate synthetase (see before) - AMP synthesis: adenylosuccinate synthetase (see later) Asn Catabolism: Synthesis: Asparaginase: Asn Asp + N 4+ (see before) Asn synthetase: Asp + Gln Asn + Glu (see before)
Glucogenic (glucoplastic) and ketogenic (ketoplastic) amino acids glucose pyruvate Acyl-CoA Asp ( Asn) OXA Acetyl-CoA Il e fumarate CAC acetoacetate b-oxidation succinylcoa akg Val, Ile Thr, Met Lys, Leu, Tyr ( Phe), Trp ketone bodies