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[[Image:2byl.gif|left|200px]]


{{Structure
==Structure of ornithine aminotransferase triple mutant Y85I Y55A G320F==
|PDB= 2byl |SIZE=350|CAPTION= <scene name='initialview01'>2byl</scene>, resolution 2.15&Aring;
<StructureSection load='2byl' size='340' side='right'caption='[[2byl]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
|SITE= <scene name='pdbsite=AC1:Plp+(Pyridoxal-5&#39;-Phosphate)+Is+Bound+To+The+Protein+Via+...'>AC1</scene>
== Structural highlights ==
|LIGAND= <scene name='pdbligand=PLP:PYRIDOXAL-5&#39;-PHOSPHATE'>PLP</scene>
<table><tr><td colspan='2'>[[2byl]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BYL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BYL FirstGlance]. <br>
|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Ornithine_aminotransferase Ornithine aminotransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.13 2.6.1.13] </span>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.15&#8491;</td></tr>
|GENE=  
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PLP:PYRIDOXAL-5-PHOSPHATE'>PLP</scene></td></tr>
|DOMAIN=
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2byl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2byl OCA], [https://pdbe.org/2byl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2byl RCSB], [https://www.ebi.ac.uk/pdbsum/2byl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2byl ProSAT]</span></td></tr>
|RELATEDENTRY=
</table>
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2byl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2byl OCA], [http://www.ebi.ac.uk/pdbsum/2byl PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2byl RCSB]</span>
== Disease ==
}}
[https://www.uniprot.org/uniprot/OAT_HUMAN OAT_HUMAN] Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:[https://omim.org/entry/258870 258870]. HOGA is a slowly progressive blinding autosomal recessive disorder.<ref>PMID:3375240</ref> <ref>PMID:2793865</ref> <ref>PMID:1612597</ref> <ref>PMID:1737786</ref> <ref>PMID:7887415</ref> <ref>PMID:7668253</ref>
== Function ==
[https://www.uniprot.org/uniprot/OAT_HUMAN OAT_HUMAN]
== Evolutionary Conservation ==
[[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/by/2byl_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/main_output.php?pdb_ID=2byl ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Ornithine aminotransferase and 4-aminobutyrate aminotransferase are related pyridoxal phosphate-dependent enzymes having different substrate specificities. The atomic structures of these enzymes have shown (i) that active site differences are limited to the steric positions occupied by two tyrosine residues in ornithine aminotransferase and (ii) that, uniquely among related, structurally characterized aminotransferases, the conserved arginine that binds the alpha-carboxylate of alpha-amino acids interacts tightly with a glutamate residue. To determine the contribution of these residues to the specificities of the enzymes, we analyzed site-directed mutants of ornithine aminotransferase by rapid reaction kinetics, x-ray crystallography, and 13C NMR spectroscopy. Mutation of one tyrosine (Tyr-85) to isoleucine, as found in aminobutyrate aminotransferase, decreased the rate of the reaction of the enzyme with ornithine 1000-fold and increased that with 4-aminobutyrate 16-fold, indicating that Tyr-85 is a major determinant of specificity toward ornithine. Unexpectedly, the limiting rate of the second half of the reaction, conversion of ketoglutarate to glutamate, was greatly increased, although the kinetics of the reverse reaction were unaffected. A mutant in which the glutamate (Glu-235) that interacts with the conserved arginine was replaced by alanine retained its regiospecificity for the delta-amino group of ornithine, but the glutamate reaction was enhanced 650-fold, whereas only a 5-fold enhancement of the ketoglutarate reaction rate resulted. A model is proposed in which conversion of the enzyme to its pyridoxamine phosphate form disrupts the internal glutamate-arginine interaction, thus enabling ketoglutarate but not glutamate to be a good substrate.


'''STRUCTURE OF ORNITHINE AMINOTRANSFERASE TRIPLE MUTANT Y85I Y55A G320F'''
Determinants of substrate specificity in omega-aminotransferases.,Markova M, Peneff C, Hewlins MJ, Schirmer T, John RA J Biol Chem. 2005 Oct 28;280(43):36409-16. Epub 2005 Aug 11. PMID:16096275<ref>PMID:16096275</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2byl" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
Ornithine aminotransferase and 4-aminobutyrate aminotransferase are related pyridoxal phosphate-dependent enzymes having different substrate specificities. The atomic structures of these enzymes have shown (i) that active site differences are limited to the steric positions occupied by two tyrosine residues in ornithine aminotransferase and (ii) that, uniquely among related, structurally characterized aminotransferases, the conserved arginine that binds the alpha-carboxylate of alpha-amino acids interacts tightly with a glutamate residue. To determine the contribution of these residues to the specificities of the enzymes, we analyzed site-directed mutants of ornithine aminotransferase by rapid reaction kinetics, x-ray crystallography, and 13C NMR spectroscopy. Mutation of one tyrosine (Tyr-85) to isoleucine, as found in aminobutyrate aminotransferase, decreased the rate of the reaction of the enzyme with ornithine 1000-fold and increased that with 4-aminobutyrate 16-fold, indicating that Tyr-85 is a major determinant of specificity toward ornithine. Unexpectedly, the limiting rate of the second half of the reaction, conversion of ketoglutarate to glutamate, was greatly increased, although the kinetics of the reverse reaction were unaffected. A mutant in which the glutamate (Glu-235) that interacts with the conserved arginine was replaced by alanine retained its regiospecificity for the delta-amino group of ornithine, but the glutamate reaction was enhanced 650-fold, whereas only a 5-fold enhancement of the ketoglutarate reaction rate resulted. A model is proposed in which conversion of the enzyme to its pyridoxamine phosphate form disrupts the internal glutamate-arginine interaction, thus enabling ketoglutarate but not glutamate to be a good substrate.
*[[Aminotransferase 3D structures|Aminotransferase 3D structures]]
 
== References ==
==About this Structure==
<references/>
2BYL is a [[Single protein]] structure of 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=2BYL OCA].
__TOC__
 
</StructureSection>
==Reference==
Determinants of substrate specificity in omega-aminotransferases., Markova M, Peneff C, Hewlins MJ, Schirmer T, John RA, J Biol Chem. 2005 Oct 28;280(43):36409-16. Epub 2005 Aug 11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/16096275 16096275]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Ornithine aminotransferase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Hewlins MJE]]
[[Category: Hewlins, M J.E.]]
[[Category: John RA]]
[[Category: John, R A.]]
[[Category: Markova M]]
[[Category: Markova, M.]]
[[Category: Peneff C]]
[[Category: Peneff, C.]]
[[Category: Schirmer T]]
[[Category: Schirmer, T.]]
[[Category: aminotransferase]]
[[Category: disease mutation]]
[[Category: mitochondrion]]
[[Category: plp-dependent enzyme]]
[[Category: polymorphism]]
[[Category: pyridoxal phosphate]]
[[Category: transferase]]
[[Category: transit peptide]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 02:13:46 2008''

Latest revision as of 16:58, 13 December 2023

Structure of ornithine aminotransferase triple mutant Y85I Y55A G320FStructure of ornithine aminotransferase triple mutant Y85I Y55A G320F

Structural highlights

2byl is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.15Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

OAT_HUMAN Defects in OAT are the cause of hyperornithinemia with gyrate atrophy of choroid and retina (HOGA) [MIM:258870. HOGA is a slowly progressive blinding autosomal recessive disorder.[1] [2] [3] [4] [5] [6]

Function

OAT_HUMAN

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 aminotransferase and 4-aminobutyrate aminotransferase are related pyridoxal phosphate-dependent enzymes having different substrate specificities. The atomic structures of these enzymes have shown (i) that active site differences are limited to the steric positions occupied by two tyrosine residues in ornithine aminotransferase and (ii) that, uniquely among related, structurally characterized aminotransferases, the conserved arginine that binds the alpha-carboxylate of alpha-amino acids interacts tightly with a glutamate residue. To determine the contribution of these residues to the specificities of the enzymes, we analyzed site-directed mutants of ornithine aminotransferase by rapid reaction kinetics, x-ray crystallography, and 13C NMR spectroscopy. Mutation of one tyrosine (Tyr-85) to isoleucine, as found in aminobutyrate aminotransferase, decreased the rate of the reaction of the enzyme with ornithine 1000-fold and increased that with 4-aminobutyrate 16-fold, indicating that Tyr-85 is a major determinant of specificity toward ornithine. Unexpectedly, the limiting rate of the second half of the reaction, conversion of ketoglutarate to glutamate, was greatly increased, although the kinetics of the reverse reaction were unaffected. A mutant in which the glutamate (Glu-235) that interacts with the conserved arginine was replaced by alanine retained its regiospecificity for the delta-amino group of ornithine, but the glutamate reaction was enhanced 650-fold, whereas only a 5-fold enhancement of the ketoglutarate reaction rate resulted. A model is proposed in which conversion of the enzyme to its pyridoxamine phosphate form disrupts the internal glutamate-arginine interaction, thus enabling ketoglutarate but not glutamate to be a good substrate.

Determinants of substrate specificity in omega-aminotransferases.,Markova M, Peneff C, Hewlins MJ, Schirmer T, John RA J Biol Chem. 2005 Oct 28;280(43):36409-16. Epub 2005 Aug 11. PMID:16096275[7]

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

See Also

References

  1. ↑ Ramesh V, McClatchey AI, Ramesh N, Benoit LA, Berson EL, Shih VE, Gusella JF. Molecular basis of ornithine aminotransferase deficiency in B-6-responsive and -nonresponsive forms of gyrate atrophy. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3777-80. PMID:3375240
  2. ↑ Inana G, Chambers C, Hotta Y, Inouye L, Filpula D, Pulford S, Shiono T. Point mutation affecting processing of the ornithine aminotransferase precursor protein in gyrate atrophy. J Biol Chem. 1989 Oct 15;264(29):17432-6. PMID:2793865
  3. ↑ Michaud J, Brody LC, Steel G, Fontaine G, Martin LS, Valle D, Mitchell G. Strand-separating conformational polymorphism analysis: efficacy of detection of point mutations in the human ornithine delta-aminotransferase gene. Genomics. 1992 Jun;13(2):389-94. PMID:1612597
  4. ↑ Brody LC, Mitchell GA, Obie C, Michaud J, Steel G, Fontaine G, Robert MF, Sipila I, Kaiser-Kupfer M, Valle D. Ornithine delta-aminotransferase mutations in gyrate atrophy. Allelic heterogeneity and functional consequences. J Biol Chem. 1992 Feb 15;267(5):3302-7. PMID:1737786
  5. ↑ Michaud J, Thompson GN, Brody LC, Steel G, Obie C, Fontaine G, Schappert K, Keith CG, Valle D, Mitchell GA. Pyridoxine-responsive gyrate atrophy of the choroid and retina: clinical and biochemical correlates of the mutation A226V. Am J Hum Genet. 1995 Mar;56(3):616-22. PMID:7887415
  6. ↑ Kobayashi T, Ogawa H, Kasahara M, Shiozawa Z, Matsuzawa T. A single amino acid substitution within the mature sequence of ornithine aminotransferase obstructs mitochondrial entry of the precursor. Am J Hum Genet. 1995 Aug;57(2):284-91. PMID:7668253
  7. ↑ Markova M, Peneff C, Hewlins MJ, Schirmer T, John RA. Determinants of substrate specificity in omega-aminotransferases. J Biol Chem. 2005 Oct 28;280(43):36409-16. Epub 2005 Aug 11. PMID:16096275 doi:10.1074/jbc.M506977200

2byl, resolution 2.15Å

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