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1c9y, resolution 1.90Å ()
Ligands: ,
Activity: Ornithine carbamoyltransferase, with EC number
Related: 1oth
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml



Publication Abstract from PubMed

The crystal structure of human ornithine transcarbamylase (OTCase) complexed with carbamoyl phosphate (CP) and L-norvaline (NOR) has been determined to 1.9-A resolution. There are significant differences in the interactions of CP with the protein, compared with the interactions of the CP moiety of the bisubstrate analogue N-(phosphonoacetyl)-L-ornithine (PALO). The carbonyl plane of CP rotates about 60 degrees compared with the equivalent plane in PALO complexed with OTCase. This positions the side chain of NOR optimally to interact with the carbonyl carbon of CP. The mixed-anhydride oxygen of CP, which is analogous to the methylene group in PALO, interacts with the guanidinium group of Arg-92; the primary carbamoyl nitrogen interacts with the main-chain carbonyl oxygens of Cys-303 and Leu-304, the side chain carbonyl oxygen of Gln-171, and the side chain of Arg-330. The residues that interact with NOR are similar to the residues that interact with the ornithine (ORN) moiety of PALO. The side chain of NOR is well defined and close to the side chain of Cys-303 with the side chains of Leu-163, Leu-200, Met-268, and Pro-305 forming a hydrophobic wall. C-delta of NOR is close to the carbonyl oxygen of Leu-304 (3.56 A), S-gamma atom of Cys-303 (4.19 A), and carbonyl carbon of CP (3.28 A). Even though the N-epsilon atom of ornithine is absent in this structure, the side chain of NOR is positioned to enable the N-epsilon of ornithine to donate a hydrogen to the S-gamma atom of Cys-303 along the reaction pathway. Binding of CP and NOR promotes domain closure to the same degree as PALO, and the active site structure of CP-NOR-enzyme complex is similar to that of the PALO-enzyme complex. The structures of the active sites in the complexes of aspartate transcarbamylase (ATCase) with various substrates or inhibitors are similar to this OTCase structure, consistent with their common evolutionary origin.

Crystal structure of human ornithine transcarbamylase complexed with carbamoyl phosphate and L-norvaline at 1.9 A resolution., Shi D, Morizono H, Aoyagi M, Tuchman M, Allewell NM, Proteins. 2000 Jun 1;39(4):271-7. PMID:10813810

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

1c9y is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.


  • Shi D, Morizono H, Aoyagi M, Tuchman M, Allewell NM. Crystal structure of human ornithine transcarbamylase complexed with carbamoyl phosphate and L-norvaline at 1.9 A resolution. Proteins. 2000 Jun 1;39(4):271-7. PMID:10813810
  • Shi D, Morizono H, Yu X, Roth L, Caldovic L, Allewell NM, Malamy MH, Tuchman M. Crystal structure of N-acetylornithine transcarbamylase from Xanthomonas campestris: a novel enzyme in a new arginine biosynthetic pathway found in several eubacteria. J Biol Chem. 2005 Apr 15;280(15):14366-9. Epub 2005 Feb 24. PMID:15731101 doi:10.1074/jbc.C500005200
  • Virnau P, Mirny LA, Kardar M. Intricate knots in proteins: Function and evolution. PLoS Comput Biol. 2006 Sep 15;2(9):e122. Epub 2006 Jul 28. PMID:16978047 doi:10.1371/journal.pcbi.0020122
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  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:http://dx.doi.org/10.1172/JCI113738
  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
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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:http://dx.doi.org/10.1002/humu.1380030415
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  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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