Dihydroorotate dehydrogenase

Dihydroorotate dehydrogenase (EC 1.3.3.1) is an enzyme that catalyzes the fourth step in the de novo biosynthesis of pyrimidine. It converts dihydroorotate to orotate:

(S)-dihydroorotate + O₂ $\rightleftharpoons$ orotate + H₂O₂

Human dihydroorotate dehydrogenase is a ubiquitous FMN flavoprotein. In bacteria (gene pyrD), it is located on the inner side of the cytosolic membrane. In some yeasts, such as in Saccharomyces cerevisiae (gene URA1), it is a cytosolic protein, whereas, in other eukaryotes, it is found in the mitochondria.^[1]

1 Human proteins containing this domain
2 Clinical significance
3 References
4 Further reading
5 External links

Human proteins containing this domain

DHODH; DPYD;

Clinical significance

The anti-inflammatory drug leflunomide has been shown to inhibit DHODH. Human DHODH has two domains: an alpha/beta-barrel domain containing the active site and an alpha-helical domain that forms the opening of a tunnel leading to the active site. Leflunomide has been shown to bind in this tunnel.^[2] Leflunomide is being used for treatment of rheumatoid and psoriatic arthritis.

Mutations in this gene have been shown to cause Miller syndrome ^[3] also known as Genee-Wiedemann syndrome, Wildervanck-Smith syndrome or post axial acrofacial dystosis (POADS).

References

^ Lacroute F, Thomas D, Nagy M (1992). "Divergent evolution of pyrimidine biosynthesis between anaerobic and aerobic yeasts". Proc. Natl. Acad. Sci. U.S.A. 89 (19): 8966–70. doi:10.1073/pnas.89.19.8966. PMC 50045. PMID 1409592. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=50045.
^ Liu S, Neidhardt EA, Grossman TH, Ocain T, Clardy J (January 2000). "Structures of human dihydroorotate dehydrogenase in complex with antiproliferative agents". Structure 8 (1): 25–33. doi:10.1016/S0969-2126(00)00077-0. PMID 10673429.
^ Ng SB, Buckingham KJ,Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ (December 2009). "Exome Sequencing identifies the cause of a mendelian disorder". Nature Genetics 42 (1): 30–5. doi:10.1038/ng.499. PMC 2847889. PMID 19915526. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2847889.

External links

MeSH dihydroorotate+dehydrogenase

Oxidoreductases: CH-CH oxidoreductases (EC 1.3)

1.3.1: NAD/NADP acceptor	Enoyl-acyl carrier protein reductase/Enoyl ACP reductase · 7-Dehydrocholesterol reductase · Biliverdin reductase · 2,4 Dienoyl-CoA reductase

1.3.3: Oxygen acceptor	Dihydroorotate dehydrogenase · Coproporphyrinogen III oxidase · Protoporphyrinogen oxidase

1.3.5: Quinone	Succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD)

1.3.99: Other acceptors	Fumarate reductase · Butyryl CoA dehydrogenase · Acyl CoA dehydrogenase (ACADSB, ACADS) · 5α-reductase (SRD5A1, SRD5A2, SRD5A3) · Glutaryl-CoA dehydrogenase · Isovaleryl coenzyme A dehydrogenase

B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6

Metabolism: amino acid metabolism · nucleotide enzymes

Purine metabolism

Anabolism	R5P->IMP: Ribose-phosphate diphosphokinase · Amidophosphoribosyltransferase · Phosphoribosylglycinamide formyltransferase · AIR synthetase (FGAM cyclase) · Phosphoribosylaminoimidazole carboxylase · Phosphoribosylaminoimidazolesuccinocarboxamide synthase · IMP synthase IMP->AMP: Adenylosuccinate synthase · Adenylosuccinate lyase · reverse (AMP deaminase) IMP->GMP: IMP dehydrogenase · GMP synthase · reverse (GMP reductase)

Nucleotide salvage	Hypoxanthine-guanine phosphoribosyltransferase · Adenine phosphoribosyltransferase

Catabolism	Adenosine deaminase · Purine nucleoside phosphorylase · Guanine deaminase · Xanthine oxidase · Urate oxidase

Pyrimidine metabolism

Anabolism	CAD (Carbamoyl phosphate synthase II, Aspartate carbamoyltransferase, Dihydroorotase) Dihydroorotate dehydrogenase · Orotidine 5'-phosphate decarboxylase/Uridine monophosphate synthetase CTP synthase

Catabolism	Dihydropyrimidine dehydrogenase · Dihydropyrimidinase/DPYS · Beta-ureidopropionase/UPB1

Deoxyribonucleotides

Ribonucleotide reductase · Nucleoside-diphosphate kinase · DCMP deaminase · Thymidylate synthase · Dihydrofolate reductase

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

Mitochondrial proteins

Outer membrane	fatty acid degradation (Carnitine palmitoyltransferase I, Long fatty acyl CoA synthetase) tryptophan metabolism (Kynureninase) monoamine neurotransmitter metabolism (Monoamine oxidase)

Intermembrane space	Adenylate kinase - Creatine kinase

Inner membrane	oxidative phosphorylation (Coenzyme Q - cytochrome c reductase, Cytochrome c, NADH dehydrogenase, Succinate dehydrogenase) pyrimidine metabolism (Dihydroorotate dehydrogenase) mitochondrial shuttle (Malate-aspartate shuttle, Glycerol phosphate shuttle) other (Glutamate aspartate transporter, Glycerol-3-phosphate dehydrogenase, ATP synthase, Carnitine palmitoyltransferase II, Uncoupling protein)

Matrix	citric acid cycle (Citrate synthase, Aconitase, Isocitrate dehydrogenase, Oxoglutarate dehydrogenase, Succinyl coenzyme A synthetase, Fumarase, Malate dehydrogenase) anaplerotic reactions (Aspartate transaminase, Glutamate dehydrogenase, Pyruvate dehydrogenase complex) urea cycle (Carbamoyl phosphate synthetase I, Ornithine transcarbamylase, N-Acetylglutamate synthase) alcohol metabolism (ALDH2) PMPCB

Other/to be sorted	steroidogenesis (Cholesterol side-chain cleavage enzyme, Steroid 11-beta-hydroxylase, Aldosterone synthase), Frataxin Mitochondrial membrane transport protein (Mitochondrial permeability transition pore, Mitochondrial carrier)

Mitochondrial DNA	Complex I (MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND4L, MT-ND5, MT-ND6) - Complex III (MT-CYB) - Complex IV (MT-CO1, MT-CO2, MT-CO3) ATP synthase (MT-ATP6, MT-ATP8) tRNA (MT-TA, MT-TC, MT-TD, MT-TE, MT-TF, MT-TG, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TP, MT-TQ, MT-TR, MT-TS1, MT-TS2, MT-TT, MT-TV, MT-TW, MT-TY)

see also mitochondrial diseases B strc: edmb (perx), skel (ctrs), epit, cili, mito, nucl (chro)

This article incorporates text from the public domain Pfam and InterPro IPR001295

Dihydroorotate dehydrogenase

Contents

Human proteins containing this domain

Clinical significance

References

Further reading

External links