Pyrimidine Metabolism

O O

O O = = = - = COO- C OO C C C C + HN CH CH HN CHCH3 HN CHCH3 H N CH H2 N CH2 2 HN 2 2 - O O = - O=C CHCOO O=C - = O=C CHCOO- O=C CHCOO OCHOND C.COO O=C C.COO- O=C CH

N IT RI N N N

O O O O O H N N A O P

2 H H M H P-O-CH 2 O -O-CH 2 O

O O O P-O O - Glutamate P H O PP H H H H HCO H O 2ADP P i Aspartate i 2 UQ UQH2 i CO 3 2 2ATP PRPP H H 2 H H 1.3.1.14 OH OH OH OH Glutamine Carbamoyl- P Carbamoylaspartate Dihydroorotate Orotate Orotidine- P Uridine -5-P 2.1.3.2 Enzyme 2.4.2.10 Bifunctional Enzyme 4.1.2.3 6.3.5.5 Trifunctional 3.5.2.3 MIT UMP P Y R I M D N E O B I O S Y N T H E CHONDRIA ATP PRPP RNA DNA NH O NH 2 DNA O ENZYMES C RNAn+1 2 C 2.7.7.7 n+1 C C N CH 2.7.7.7 T E S CH HN 2.7.7.6 2.7.7.6 N CH HN CCH3 1.2.1.18 Malonate semialdehyde dehydrogenase (acetylating) O=C CH RNA O=C CH DNAn O=C CH n O=C CH N N I N N 1.3.1.2 Dihydropyrimidine dehydrogenase Ribose-P-O-P-O-P Deoxyribose- P-O-P-O-P Deoxyribose-P-O-P-O-P (NADP+) 6.3.4.2 Ribose-P- O-P-O-P Uridine triphosphate Cytidine triphosphate Deoxycytidine triphosphate Thymidinetriphosphate 1.3.1.14 Orotate reductase (NADH)

T R I P H O S A 1.6.4.5 Thioredoxin reductase (NADPH) N U C L E O S I D UTP ATP CTP dCTP dTTP 1.17.4.1 Ribonucleoside-diphosphate Pi Glutamate ADP + Glutamine + O reductase (NADPH) O NADP NADPH+H H O NH2 2 ADP NH C 2.1.1.45 Thymidylate synthase C H O C 2 2 ADP H2O ADP 3.6.1.15 2.7.4.6 C HN CCH H2O ADP 2.1.3.2 Aspartate carbamoyltransferase HN CH N CH 1.6.4.5 3 T E S 2.7.4.6 P N CH 3.6.1.15 3.6.1.15 3.6.1.15 2.7.4.6 i ATP 2.7.4.6 2.3.2.23 Deoxyuridine phosphorylase O=C CH P O=C CH i ATP O=C CH Pi ATP O=C CH N Pi ATP 2.4.2.- Pentosyltransferase N P- O-P-O-CH N N 2 (S-S) P- O-P-O-CH2 Deoxyribose-P-O-P 2.4.2.2 Pyrimidine-nucleoside phosphorylase Ribose- P- O-P (2SH) Deoxycytidine Thymidine diphosphate 2.4.2.3 Uridine (pyrimidine) phosphorylase Uridinediphosphate H H Cytidined iphosphate T diphosphate H H H hi i n 2.4.2.4 Thymidine phosphorylase D I P H O S A H o x H redo H dTDP 2.4.2.9 Uracil phosphoribosyltransferase N U C L E O S I D UDP CDP 1.17.4.1 dCDP dTMP OH OH OH H O 2.4.2.10 Orotate phosphoribosyltransferase C O THF 2.4.2.23 Deoxyuridine phosphorylase C H O ADP N CH H O ADP T E S 2 H O ADP H O ADP 2 2.6.1.18 3-Alanine-pyruvate transaminase HN CH 2 2 3.6.1.6 2.7.4.4 3.6.1.6 2.7.4.4 5 10 3.6.1.6 2.7.4.4 O 3.6.1.6 2.7.4.4 NH2 O=C CH 2.6.1.22 3-Amino-2-methylpropionate NH N N-Methylene- = P 2 C N P transaminase O=C CH i ATP C Pi ATP Pi ATP H4Folate i ATP C N CH N CH HN CCH 2.7.1.21 Thymidine kinase HN DeoxyriboseP- Dihydrofolate 3 Ribose-P 2.7.1.48 Uridine kinase Uridine-P O=C CH Cytidine-P O=C CH Deoxycytidine-P Deoxyuridine-P Thymidine-P O=C CH N N N 2.7.1.74 Deoxycytidine kinase Deoxyribose-P dCMP dUMP dTMP 2.7.4.4 Nucleoside-phosphate kinase

N U C L E O S I D CMP Deoxyribose-P

M O N P H S A UMP Ribose-P PPi 3.5.4.12 2.1.1.45 2.7.4.6 Nucleoside-diphosphate kinase 2.4.2.9 H Oi ADP 3.1.3.31 Nucleotidase 2 H O + H2O O NH2 ADP NH ADP 3.5.1.6 3-Ureidopropionase PRPP C 3.1.3.31 2 H O ADP 2 NH4 2.7.1.48 H O H O S S 2 C 2 ADP 2.7.1.74 C 3.1.3.31 2 2.7.1.48 A A 3.1.3.31 3.5.2.2 Dihydropyrimidinase HN CH 3.1.3.31 2.7.1.48 HN CH Pi N CH 2.7.1.74 P ATP O 3.1.3.31 L L i C O V ATP V P ATP 3.5.2.3 Dihydroorotase - i ATP P C P A A i O=C CH i ATP O=C CH O=C CH HN CH G G HN CCH 3.5.4.1 Cytosine deaminase

N N- N 3 E E 3.5.4.5 Cytidine deaminase

P Y R I M D N E O=C CH 3.5.4.5 - O=C N U C L E O S I D Ribose Ribose N CH Uridine Cytidine Ribose Deoxycytidine Deoxyuridine Thymidine N 3.5.4.12 dCMP deaminase Deoxyribose 3.5.4.14 Deoxycytidine deaminase NH2 3.5.4.14 Deoxyribose O P C C i P 3.6.1.6 Nucleoside-diphosphatase 2.4.2.3 P CH + i HN CH i N PP H2O NH 2.4.2.4 O = 3.6.1.15 Nucleoside-triphosphatase Ribose-1-P H O NH + i 4 2 4 2.4.2.3 O=C C 4.1.1.23 Orotidine-5-phosphate O=C CH CH 2.4.2.9 Ribose-1-P Ribose-1-P N Deoxyribose-1-P P HN CCH3 decarboxylase N H i 6.3.4.2 CTP synthase H 3.5.4.1 PRPP O=C CH Cytosine 2.4.2.3 Thymine N 6.3.5.5 Carbamoylphosphate synthase

B A S E Uracil H (glutamine-hydrolysing)

+ COO - - O NADPH+H CCOO H N C NAD(P)H CH2 2 CH2 NAD(P) HN CH2 1.3.1.2 1.3.1.2 HSCoA CH O=C CH CO2 2 2 O=C CH2 - - H2N N CH3 COO OHCCH 2COO N 2.6.1.18 3.5.1.6 H H Acetyl-CoA Malonate 3--Alanine 3-Ureidopropionate Dihydrouracil NADP+ 1.2.1.18 - T I O N semialdehyde COO- COO O C C C CHCH 3 H2N CHCH3 HN CHCH Alanine Pyruvate CO 3 CH3 NH3 2 H2O - - CH O=C CH COO - 2 2 O=C CH2

P Y R I M D N E CH OOCCH 2 2 OHCCHCOO N D E G R A H2N N N H H Succinyl-CoA M e t h y l m a lo n a t e 2.6.1.22 3-Aminoisobutyrate 3-Ureidoisobutyrate Dihydrothymine semialdehyde 3.5.1.6