7ta1

From Proteopedia

(Difference between revisions)

Revision as of 17:02, 18 October 2023

Human Ornithine Aminotransferase (hOAT) soaked with gamma-Aminobutyric acid

Structural highlights

7ta1 is a 6 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 2.2Å
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

Publication Abstract from PubMed

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and occurs predominantly in patients with underlying chronic liver diseases. Over the past decade, human ornithine aminotransferase (hOAT), which is an enzyme that catalyzes the metabolic conversion of ornithine into an intermediate for proline or glutamate synthesis, has been found to be overexpressed in HCC cells. hOAT has since emerged as a promising target for novel anticancer therapies, especially for the ongoing rational design effort to discover mechanism-based inactivators (MBIs). Despite the significance of hOAT in human metabolism and its clinical potential as a drug target against HCC, there are significant knowledge deficits with regard to its catalytic mechanism and structural characteristics. Ongoing MBI design efforts require in-depth knowledge of the enzyme active site, in particular, pKa values of potential nucleophiles and residues necessary for the molecular recognition of ligands. Here, we conducted a study detailing the fundamental active site properties of hOAT using stopped-flow spectrophotometry and X-ray crystallography. Our results quantitatively revealed the pH-dependence of the multi-step reaction mechanism and illuminated the roles of ornithine alpha- and delta-amino groups in substrate recognition and in facilitating catalytic turnover. These findings provided insights of the catalytic mechanism that could benefit the rational design of MBIs against hOAT. In addition, hOAT's substrate recognition and turnover of several fragment-sized alternative substrates, which could serve as structural templates for MBI design, were also elucidated.

Determination of the pH-Dependence, Substrate Specificity and Turnovers of Alternative Substrates for Human Ornithine Aminotransferase.,Butrin A, Butrin A, Wawrzak Z, Moran G, Liu D J Biol Chem. 2022 Apr 20:101969. doi: 10.1016/j.jbc.2022.101969. PMID:35460691^[7]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Butrin A, Butrin A, Wawrzak Z, Moran G, Liu D. Determination of the pH-Dependence, Substrate Specificity and Turnovers of Alternative Substrates for Human Ornithine Aminotransferase. J Biol Chem. 2022 Apr 20:101969. doi: 10.1016/j.jbc.2022.101969. PMID:35460691 doi:http://dx.doi.org/10.1016/j.jbc.2022.101969

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7ta1"

Categories: Homo sapiens | Large Structures | Butrin A | Liu D | Wawrzak Z

@@ Line 3: / Line 3: @@
 <StructureSection load='7ta1' size='340' side='right'caption='[[7ta1]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7ta1]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TA1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TA1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7ta1]] is a 6 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=7TA1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TA1 FirstGlance]. <br>
-</td></tr><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>, <scene name='pdbligand=PLZ:4-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]BUTANOIC+ACID'>PLZ</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Ornithine_aminotransferase Ornithine aminotransferase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.6.1.13 2.6.1.13] </span></td></tr>
+<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>, <scene name='pdbligand=PLZ:4-[({3-HYDROXY-2-METHYL-5-[(PHOSPHONOOXY)METHYL]PYRIDIN-4-YL}METHYL)AMINO]BUTANOIC+ACID'>PLZ</scene></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7ta1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ta1 OCA], [https://pdbe.org/7ta1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ta1 RCSB], [https://www.ebi.ac.uk/pdbsum/7ta1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ta1 ProSAT]</span></td></tr>
 </table>
 == 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>
+[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]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Ornithine aminotransferase]]
+[[Category: Butrin A]]
-[[Category: Butrin, A]]
+[[Category: Liu D]]
-[[Category: Liu, D]]
+[[Category: Wawrzak Z]]
-[[Category: Wawrzak, Z]]
-[[Category: Gaba]]
-[[Category: Gamma-aminobutyric acid]]
-[[Category: Hoat]]
-[[Category: Human ornithine aminotransferase]]
-[[Category: Oat]]
-[[Category: Plp]]
-[[Category: Soaking]]
-[[Category: Transferase]]

7ta1

From Proteopedia

Revision as of 17:02, 18 October 2023

Human Ornithine Aminotransferase (hOAT) soaked with gamma-Aminobutyric acid

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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