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1oth, resolution 1.85Å ()
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml



Publication Abstract from PubMed

The crystal structure of human ornithine transcarbamoylase complexed with the bisubstrate analog N-phosphonacetyl-L-ornithine has been solved at 1.85-A resolution by molecular replacement. Deleterious mutations produce clinical hyperammonia that, if untreated, results in neurological symptoms or death (ornithine transcarbamylase deficiency). The holoenzyme is trimeric, and as in other transcarbamoylases, each subunit contains an N-terminal domain that binds carbamoyl phosphate and a C-terminal domain that binds L-ornithine. The active site is located in the cleft between domains and contains additional residues from an adjacent subunit. Binding of N-phosphonacetyl-L-ornithine promotes domain closure. The resolution of the structure enables the role of active site residues in the catalytic mechanism to be critically examined. The side chain of Cys-303 is positioned so as to be able to interact with the delta-amino group of L-ornithine which attacks the carbonyl carbon of carbamoyl phosphate in the enzyme-catalyzed reaction. This sulfhydryl group forms a charge relay system with Asp-263 and the alpha-amino group of L-ornithine, instead of with His-302 and Glu-310, as previously proposed. In common with other ureotelic ornithine transcarbamoylases, the human enzyme lacks a loop of approximately 20 residues between helix H10 and beta-strand B10 which is present in prokaryotic ornithine transcarbamoylases but has a C-terminal extension of 10 residues that interacts with the body of the protein but is exposed. The sequence of this C-terminal extension is homologous to an interhelical loop found in several membrane proteins, including mitochondrial transport proteins, suggesting a possible mode of interaction with the inner mitochondrial membrane.

1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency., Shi D, Morizono H, Ha Y, Aoyagi M, Tuchman M, Allewell NM, J Biol Chem. 1998 Dec 18;273(51):34247-54. PMID:9852088

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.


[OTC_HUMAN] Defects in OTC are the cause of ornithine carbamoyltransferase deficiency (OTCD) [MIM:311250]. OTCD is an X-linked disorder of the urea cycle which causes a form of hyperammonemia. Mutations with no residual enzyme activity are always expressed in hemizygote males by a very severe neonatal hyperammonemic coma that generally proves to be fatal. Heterozygous females are either asymptomatic or express orotic aciduria spontaneously or after protein intake. The disorder is treatable with supplemental dietary arginine and low protein diet. The arbitrary classification of patients into the 'neonatal' group (clinical hyperammonemia in the first few days of life) and 'late' onset (clinical presentation after the neonatal period) has been used to differentiate severe from mild forms.[1][2][3][4][5][6][7][8][9][10][11][12][13][14][:][15][16][17][18][19][20][21][22][23][24][:][25][26][27][28]

About this Structure

1oth is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.


  • Shi D, Morizono H, Ha Y, Aoyagi M, Tuchman M, Allewell NM. 1.85-A resolution crystal structure of human ornithine transcarbamoylase complexed with N-phosphonacetyl-L-ornithine. Catalytic mechanism and correlation with inherited deficiency. J Biol Chem. 1998 Dec 18;273(51):34247-54. PMID:9852088
  1. Gilbert-Dussardier B, Rabier D, Strautnieks S, Segues B, Bonnefont JP, Munnich A. A novel arginine (245) to glutamine change in exon 8 of the ornithine carbamoyl transferase gene in two unrelated children presenting with late onset deficiency and showing the same enzymatic pattern. Hum Mol Genet. 1994 May;3(5):831-2. PMID:8081373
  2. Maddalena A, Spence JE, O'Brien WE, Nussbaum RL. Characterization of point mutations in the same arginine codon in three unrelated patients with ornithine transcarbamylase deficiency. J Clin Invest. 1988 Oct;82(4):1353-8. PMID:3170748 doi:
  3. Grompe M, Muzny DM, Caskey CT. Scanning detection of mutations in human ornithine transcarbamoylase by chemical mismatch cleavage. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5888-92. PMID:2474822
  4. Finkelstein JE, Francomano CA, Brusilow SW, Traystman MD. Use of denaturing gradient gel electrophoresis for detection of mutation and prospective diagnosis in late onset ornithine transcarbamylase deficiency. Genomics. 1990 Jun;7(2):167-72. PMID:2347583
  5. Grompe M, Caskey CT, Fenwick RG. Improved molecular diagnostics for ornithine transcarbamylase deficiency. Am J Hum Genet. 1991 Feb;48(2):212-22. PMID:1671317
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  8. Tsai MY, Holzknecht RA, Tuchman M. Single-strand conformational polymorphism and direct sequencing applied to carrier testing in families with ornithine transcarbamylase deficiency. Hum Genet. 1993 May;91(4):321-5. PMID:8099056
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  10. Matsuura T, Hoshide R, Kiwaki K, Komaki S, Koike E, Endo F, Oyanagi K, Suzuki Y, Kato I, Ishikawa K, et al.. Four newly identified ornithine transcarbamylase (OTC) mutations (D126G, R129H, I172M and W332X) in Japanese male patients with early-onset OTC deficiency. Hum Mutat. 1994;3(4):402-6. PMID:8081398 doi:
  11. Tuchman M, Plante RJ, McCann MT, Qureshi AA. Seven new mutations in the human ornithine transcarbamylase gene. Hum Mutat. 1994;4(1):57-60. PMID:7951259 doi:
  12. Garcia-Perez MA, Paz Briones PS, Garcia-Munnoz MJ, Rubio V. A splicing mutation, a nonsense mutation (Y167X) and two missense mutations (I159T and A209V) in Spanish patients with ornithine transcarbamylase deficiency. Hum Genet. 1995 Nov;96(5):549-51. PMID:8530002
  13. Zimmer KP, Matsuura T, Colombo JP, Koch HG, Ullrich K, Deufel T, Harms E, Matsuda I. A novel point mutation at codon 269 of the ornithine transcarbamylase (OTC) gene causing neonatal onset of OTC deficiency. J Inherit Metab Dis. 1995;18(3):356-7. PMID:7474905
  14. Gilbert-Dussardier B, Segues B, Rozet JM, Rabier D, Calvas P, de Lumley L, Bonnefond JP, Munnich A. Partial duplication [dup. TCAC (178)] and novel point mutations (T125M, G188R, A209V, and H302L) of the ornithine transcarbamylase gene in congenital hyperammonemia. Hum Mutat. 1996;8(1):74-6. PMID:8807340 doi:<74::AID-HUMU11>3.0.CO;2-O 10.1002/(SICI)1098-1004(1996)8:1<74::AID-HUMU11>3.0.CO;2-O
  15. Oppliger Leibundgut EO, Wermuth B, Colombo JP, Liechti-Gallati S. Ornithine transcarbamylase deficiency: characterization of gene mutations and polymorphisms. Hum Mutat. 1996;8(4):333-9. PMID:8956038 doi:<333::AID-HUMU6>3.0.CO;2-8 10.1002/(SICI)1098-1004(1996)8:4<333::AID-HUMU6>3.0.CO;2-8
  16. Segues B, Veber PS, Rabier D, Calvas P, Saudubray JM, Gilbert-Dussardier B, Bonnefont JP, Munnich A. A 3-base pair in-frame deletion in exon 8 (delGlu272/273) of the ornithine transcarbamylase gene in late-onset hyperammonemic coma. Hum Mutat. 1996;8(4):373-4. PMID:8956045 doi:<373::AID-HUMU13>3.0.CO;2-# 10.1002/(SICI)1098-1004(1996)8:4<373::AID-HUMU13>3.0.CO;2-#
  17. Yoo HW, Kim GH, Lee DH. Identification of new mutations in the ornithine transcarbamylase (OTC) gene in Korean families. J Inherit Metab Dis. 1996;19(1):31-42. PMID:8830175
  18. Matsuda I, Tanase S. The ornithine transcarbamylase (OTC) gene: mutations in 50 Japanese families with OTC deficiency. Am J Med Genet. 1997 Sep 5;71(4):378-83. PMID:9286441
  19. Morizono H, Tuchman M, Rajagopal BS, McCann MT, Listrom CD, Yuan X, Venugopal D, Barany G, Allewell NM. Expression, purification and kinetic characterization of wild-type human ornithine transcarbamylase and a recurrent mutant that produces 'late onset' hyperammonaemia. Biochem J. 1997 Mar 1;322 ( Pt 2):625-31. PMID:9065786
  20. Oppliger Leibundgut E, Liechti-Gallati S, Colombo JP, Wermuth B. Ornithine transcarbamylase deficiency: ten new mutations and high proportion of de novo mutations in heterozygous females. Hum Mutat. 1997;9(5):409-11. PMID:9143919 doi:<409::AID-HUMU5>3.0.CO;2-Z 10.1002/(SICI)1098-1004(1997)9:5<409::AID-HUMU5>3.0.CO;2-Z
  21. Tuchman M, Morizono H, Rajagopal BS, Plante RJ, Allewell NM. Identification of 'private' mutations in patients with ornithine transcarbamylase deficiency. J Inherit Metab Dis. 1997 Aug;20(4):525-7. PMID:9266388
  22. Shimadzu M, Matsumoto H, Matsuura T, Kobayashi K, Komaki S, Kiwaki K, Hoshide R, Endo F, Saheki T, Matsuda I. Ten novel mutations of the ornithine transcarbamylase (OTC) gene in OTC deficiency. Hum Mutat. 1998;Suppl 1:S5-7. PMID:9452024
  23. Calvas P, Segues B, Rozet JM, Rabier D, Bonnefond JP, Munnich A. Novel intragenic deletions and point mutations of the ornithine transcarbamylase gene in congenital hyperammonemia. Hum Mutat. 1998;Suppl 1:S81-4. PMID:9452049
  24. Nishiyori A, Yoshino M, Tananari Y, Matsuura T, Hoshide R, Mastuda I, Mori M, Kato H. Y55D mutation in ornithine transcarbamylase associated with late-onset hyperammonemia in a male. Hum Mutat. 1998;Suppl 1:S131-3. PMID:9452065
  25. Climent C, Garcia-Perez MA, Sanjurjo P, Ruiz-Sanz JI, Vilaseca MA, Pineda M, Campistol J, Rubio V. Identification of a cytogenetic deletion and of four novel mutations (Q69X, I172F, G188V, G197R) affecting the gene for ornithine transcarbamylase (OTC) in Spanish patients with OTC deficiency. Hum Mutat. 1999 Oct;14(4):352-3. PMID:10502831 doi:<352::AID-HUMU15>3.0.CO;2-D 10.1002/(SICI)1098-1004(199910)14:4<352::AID-HUMU15>3.0.CO;2-D
  26. Popowska E, Ciara E, Rokicki D, Pronicka E. Three novel and one recurrent ornithine carbamoyltransferase gene mutations in Polish patients. J Inherit Metab Dis. 1999 Feb;22(1):92-3. PMID:10070627
  27. Giorgi M, Morrone A, Donati MA, Ciani F, Bardelli T, Biasucci G, Zammarchi E. Lymphocyte mRNA analysis of the ornithine transcarbamylase gene in Italian OTCD male patients and manifesting carriers: identification of novel mutations. Hum Mutat. 2000 Apr;15(4):380-1. PMID:10737985 doi:<380::AID-HUMU12>3.0.CO;2-Q 10.1002/(SICI)1098-1004(200004)15:4<380::AID-HUMU12>3.0.CO;2-Q
  28. Climent C, Rubio V. Identification of seven novel missense mutations, two splice-site mutations, two microdeletions and a polymorphic amino acid substitution in the gene for ornithine transcarbamylase (OTC) in patients with OTC deficiency. Hum Mutat. 2002 Feb;19(2):185-6. PMID:11793483 doi:10.1002/humu.9011

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