| Structural highlights
Disease
[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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Ornithine transcarbamoylase from ovine liver has been purified to homogeneity. Like all anabolic OTCs, the ovine enzyme is a trimer, constituted by identical subunits of 34 kDa. Sequence analysis of the 54 N-terminal residues of ovine OTC shows a high degree of homology with the human enzyme. The optimum pH and the Michaelis constants for the catalytic reaction were determined. The ovine enzyme is the most thermostable one among mammals OTCs, its critical temperature being 6 degrees C higher than those measured for the other enzymes. The enzyme has been crystallised and the structure determined at 3.5 A resolution. Crystals belong to the cubic P4(3)32 space group, with a = b = c = 184.7 A and a solvent content of about 80%. There is no evidence of any ligand in the active site cavity, indicating that the crystals contain an unliganded or T state of the enzyme. The unliganded OTCase enzyme adopts a trimeric structure which, in the crystal, presents a three-fold axis coincident with the crystallographic one. The conformation of each monomer in the trimer is quite similar to that of the liganded human protein, with the exception of a few loops, directly interacting with the substrate(s), which are able to induce a rearrangement of the quaternary organisation of the trimer, that accounts for the cooperative behaviour of the enzyme following the binding of the substrates.
Functional and structural characterization of ovine ornithine transcarbamoylase.,De Gregorio A, Battistutta R, Arena N, Panzalorto M, Francescato P, Valentini G, Bruno G, Zanotti G Org Biomol Chem. 2003 Sep 21;1(18):3178-85. PMID:14527149[29]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Hentzen D, Pelet A, Feldman D, Rabier D, Berthelot J, Munnich A. Fatal hyperammonemia resulting from a C-to-T mutation at a MspI site of the ornithine transcarbamylase gene. Hum Genet. 1991 Dec;88(2):153-6. PMID:1721894
- ↑ Tuchman M, Holzknecht RA, Gueron AB, Berry SA, Tsai MY. Six new mutations in the ornithine transcarbamylase gene detected by single-strand conformational polymorphism. Pediatr Res. 1992 Nov;32(5):600-4. PMID:1480464 doi:http://dx.doi.org/10.1203/00006450-199211000-00024
- ↑ 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
- ↑ Tuchman M, Plante RJ, Giguere Y, Lemieux B. The ornithine transcarbamylase gene: new "private" mutations in four patients and study of a polymorphism. Hum Mutat. 1994;3(3):318-20. PMID:8019569 doi:http://dx.doi.org/10.1002/humu.1380030325
- ↑ 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
- ↑ 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:http://dx.doi.org/10.1002/humu.1380040109
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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-#
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ De Gregorio A, Battistutta R, Arena N, Panzalorto M, Francescato P, Valentini G, Bruno G, Zanotti G. Functional and structural characterization of ovine ornithine transcarbamoylase. Org Biomol Chem. 2003 Sep 21;1(18):3178-85. PMID:14527149
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