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==Crystal structure of human 1-pyrroline-5-carboxylate dehydrogenase mutant S352L==
==Crystal structure of human 1-pyrroline-5-carboxylate dehydrogenase mutant S352L==
<StructureSection load='3v9i' size='340' side='right' caption='[[3v9i]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
<StructureSection load='3v9i' size='340' side='right'caption='[[3v9i]], [[Resolution|resolution]] 2.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[3v9i]] is a 4 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=3V9I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3V9I FirstGlance]. <br>
<table><tr><td colspan='2'>[[3v9i]] is a 4 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=3V9I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3V9I FirstGlance]. <br>
</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v9g|3v9g]], [[3v9h|3v9h]], [[3v9j|3v9j]], [[3v9k|3v9k]], [[3v9l|3v9l]]</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]] 2.85&#8491;</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ALDH4, ALDH4A1, P5CDH ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3v9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v9i OCA], [https://pdbe.org/3v9i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3v9i RCSB], [https://www.ebi.ac.uk/pdbsum/3v9i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3v9i ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/1-pyrroline-5-carboxylate_dehydrogenase 1-pyrroline-5-carboxylate dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.5.1.12 1.5.1.12] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3v9i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v9i OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3v9i RCSB], [http://www.ebi.ac.uk/pdbsum/3v9i PDBsum]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/AL4A1_HUMAN AL4A1_HUMAN]] Hyperprolinemia type 2. The disease is caused by mutations affecting the gene represented in this entry.  
[https://www.uniprot.org/uniprot/AL4A1_HUMAN AL4A1_HUMAN] Hyperprolinemia type 2. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/AL4A1_HUMAN AL4A1_HUMAN]] Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.<ref>PMID:22516612</ref> 
[https://www.uniprot.org/uniprot/AL4A1_HUMAN AL4A1_HUMAN] Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.<ref>PMID:22516612</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Type II hyperprolinemia is an autosomal recessive disorder caused by a deficiency in Delta(1)-pyrroline-5-carboxylate dehydrogenase (P5CDH; also known as ALDH4A1), the aldehyde dehydrogenase that catalyzes the oxidation of glutamate semialdehyde to glutamate. Here, we report the first structure of human P5CDH (HsP5CDH) and investigate the impact of the hyperprolinemia-associated mutation of Ser352 to Leu on the structure and catalytic properties of the enzyme. The 2. 5-A-resolution crystal structure of HsP5CDH was determined using experimental phasing. Structures of the mutant enzymes S352A (2.4 A) and S352L (2.85 A) were determined to elucidate the structural consequences of altering Ser352. Structures of the 93% identical mouse P5CDH complexed with sulfate ion (1.3 A resolution), glutamate (1.5 A), and NAD(+) (1.5 A) were determined to obtain high-resolution views of the active site. Together, the structures show that Ser352 occupies a hydrophilic pocket and is connected via water-mediated hydrogen bonds to catalytic Cys348. Mutation of Ser352 to Leu is shown to abolish catalytic activity and eliminate NAD(+) binding. Analysis of the S352A mutant shows that these functional defects are caused by the introduction of the nonpolar Leu352 side chain rather than the removal of the Ser352 hydroxyl. The S352L structure shows that the mutation induces a dramatic 8-A rearrangement of the catalytic loop. Because of this conformational change, Ser349 is not positioned to interact with the aldehyde substrate, conserved Glu447 is no longer poised to bind NAD(+), and Cys348 faces the wrong direction for nucleophilic attack. These structural alterations render the enzyme inactive.
 
The Three-Dimensional Structural Basis of Type II Hyperprolinemia.,Srivastava D, Singh RK, Moxley MA, Henzl MT, Becker DF, Tanner JJ J Mol Biol. 2012 Apr 16. PMID:22516612<ref>PMID:22516612</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>


==See Also==
==See Also==
*[[Aldehyde dehydrogenase 3D structures|Aldehyde dehydrogenase 3D structures]]
*[[Pyrroline-5-carboxylate dehydrogenase|Pyrroline-5-carboxylate dehydrogenase]]
*[[Pyrroline-5-carboxylate dehydrogenase|Pyrroline-5-carboxylate dehydrogenase]]
== References ==
== References ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: 1-pyrroline-5-carboxylate dehydrogenase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Singh, R K]]
[[Category: Large Structures]]
[[Category: Tanner, J J]]
[[Category: Singh RK]]
[[Category: Acting on aldehyde or oxo group of donor]]
[[Category: Tanner JJ]]
[[Category: Aldehyde dehydrogenase]]
[[Category: Mitochondria]]
[[Category: Nad or nadp as acceptor]]
[[Category: Nucleotide binding]]
[[Category: Oxidoreductase]]
[[Category: Rossmann fold]]

Latest revision as of 17:21, 14 March 2024

Crystal structure of human 1-pyrroline-5-carboxylate dehydrogenase mutant S352LCrystal structure of human 1-pyrroline-5-carboxylate dehydrogenase mutant S352L

Structural highlights

3v9i is a 4 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 2.85Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AL4A1_HUMAN Hyperprolinemia type 2. The disease is caused by mutations affecting the gene represented in this entry.

Function

AL4A1_HUMAN Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.[1]

See Also

References

  1. ↑ Srivastava D, Singh RK, Moxley MA, Henzl MT, Becker DF, Tanner JJ. The Three-Dimensional Structural Basis of Type II Hyperprolinemia. J Mol Biol. 2012 Apr 16. PMID:22516612 doi:10.1016/j.jmb.2012.04.010

3v9i, resolution 2.85Å

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