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{{STRUCTURE_1c9y|  PDB=1c9y  |  SCENE=  }}
==HUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION AND CATALYTIC MECHANISM==
===HUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION AND CATALYTIC MECHANISM===
<StructureSection load='1c9y' size='340' side='right' caption='[[1c9y]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
{{ABSTRACT_PUBMED_10813810}}
== Structural highlights ==
<table><tr><td colspan='2'>[[1c9y]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C9Y OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1C9Y FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CP:PHOSPHORIC+ACID+MONO(FORMAMIDE)ESTER'>CP</scene>, <scene name='pdbligand=NVA:NORVALINE'>NVA</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1oth|1oth]]</td></tr>
<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ornithine_carbamoyltransferase Ornithine carbamoyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.3.3 2.1.3.3] </span></td></tr>
<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1c9y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1c9y OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1c9y RCSB], [http://www.ebi.ac.uk/pdbsum/1c9y PDBsum]</span></td></tr>
<table>
== Disease ==
[[http://www.uniprot.org/uniprot/OTC_HUMAN OTC_HUMAN]] Defects in OTC are the cause of ornithine carbamoyltransferase deficiency (OTCD) [MIM:[http://omim.org/entry/311250 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.<ref>PMID:8081373</ref> <ref>PMID:3170748</ref> <ref>PMID:2474822</ref> <ref>PMID:2347583</ref> <ref>PMID:1671317</ref> <ref>PMID:1721894</ref> <ref>PMID:1480464</ref> <ref>PMID:8099056</ref> <ref>PMID:8019569</ref> <ref>PMID:8081398</ref> <ref>PMID:7951259</ref> <ref>PMID:8530002</ref> <ref>PMID:7474905</ref> <ref>PMID:8807340</ref> [:]<ref>PMID:8956038</ref> <ref>PMID:8956045</ref> <ref>PMID:8830175</ref> <ref>PMID:9286441</ref> <ref>PMID:9065786</ref> <ref>PMID:9143919</ref> <ref>PMID:9266388</ref> <ref>PMID:9452024</ref> <ref>PMID:9452049</ref> <ref>PMID:9452065</ref> [:]<ref>PMID:10502831</ref> <ref>PMID:10070627</ref> <ref>PMID:10737985</ref> <ref>PMID:11793483</ref> 
== Function ==


==Disease==
== Evolutionary Conservation ==
[[http://www.uniprot.org/uniprot/OTC_HUMAN OTC_HUMAN]] Defects in OTC are the cause of ornithine carbamoyltransferase deficiency (OTCD) [MIM:[http://omim.org/entry/311250 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.<ref>PMID:8081373</ref><ref>PMID:3170748</ref><ref>PMID:2474822</ref><ref>PMID:2347583</ref><ref>PMID:1671317</ref><ref>PMID:1721894</ref><ref>PMID:1480464</ref><ref>PMID:8099056</ref><ref>PMID:8019569</ref><ref>PMID:8081398</ref><ref>PMID:7951259</ref><ref>PMID:8530002</ref><ref>PMID:7474905</ref><ref>PMID:8807340</ref>[:]<ref>PMID:8956038</ref><ref>PMID:8956045</ref><ref>PMID:8830175</ref><ref>PMID:9286441</ref><ref>PMID:9065786</ref><ref>PMID:9143919</ref><ref>PMID:9266388</ref><ref>PMID:9452024</ref><ref>PMID:9452049</ref><ref>PMID:9452065</ref>[:]<ref>PMID:10502831</ref><ref>PMID:10070627</ref><ref>PMID:10737985</ref><ref>PMID:11793483</ref>  
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c9/1c9y_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== 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.


==About this Structure==
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<ref>PMID:10813810</ref>
[[1c9y]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1C9Y OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
<ref group="xtra">PMID:010813810</ref><ref group="xtra">PMID:015731101</ref><ref group="xtra">PMID:016978047</ref><references group="xtra"/><references/>
</div>
 
==See Also==
*[[Ornithine carbamoyltransferase|Ornithine carbamoyltransferase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Ornithine carbamoyltransferase]]
[[Category: Ornithine carbamoyltransferase]]

Revision as of 19:58, 29 September 2014

HUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION AND CATALYTIC MECHANISMHUMAN ORNITHINE TRANSCARBAMYLASE: CRYSTALLOGRAPHIC INSIGHTS INTO SUBSTRATE RECOGNITION AND CATALYTIC MECHANISM

Structural highlights

1c9y is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Related:1oth
Activity:Ornithine carbamoyltransferase, with EC number 2.1.3.3
Resources:FirstGlance, OCA, RCSB, PDBsum

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]

Function

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

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[29]

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

See Also

References

  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: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
  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
  6. ↑ 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
  7. ↑ 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
  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
  9. ↑ 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
  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
  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:http://dx.doi.org/10.1002/humu.1380040109
  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
  29. ↑ 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

1c9y, resolution 1.90Å

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