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| {{enzyme
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| | Name = Glycerate Dehydrogenase
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| | EC_number = 1.1.1.29
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| | CAS_number = 9028-37-9
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| | IUBMB_EC_number = 1/1/1/29
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| | GO_code = 0008465
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| | image = Glyoxylate Reductase Hydroxypyruvate Reductase.png
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| | width =
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| | caption = Glyoxylate Reductase/Hydroxypyruvate Reductase. Quaternary structure of 2 homodimers of GRHPR bound to NADPH and (D)-glycerate.
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| }}
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| In [[enzymology]], a '''glycerate dehydrogenase''' ({{EC number|1.1.1.29}}) is an [[enzyme]] that [[catalysis|catalyzes]] the [[chemical reaction]]
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| :(D)-glycerate + NAD<sup>+</sup> <math>\rightleftharpoons</math> hydroxypyruvate + NADH + H<sup>+</sup>
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| Thus, the two [[substrate (biochemistry)|substrates]] of this enzyme are [[(R)-glycerate]] and [[nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], whereas its 3 [[product (chemistry)|products]] are [[hydroxypyruvate]], [[nicotinamide adenine dinucleotide|NADH]], and [[hydrogen ion|H<sup>+</sup>]]. However, in nature these enzymes have the ability to catalyze the reverse reaction as well. That is, hydroxypyruvate, NADH, and H<sup>+</sup> can act as the substrates while (R)-glycerate and NAD<sup>+</sup> are formed as products. Additionally, [[nicotinamide adenine dinucleotide phosphate|NADPH]] can take the place of NADH in this reaction.<ref name="pmid2689175">{{cite journal |last=Schaftingen|first=Emile|coauthors=Fancois Van Hoof|title=Coenzyme Specificity of Mammalian liver D-glycerate dehydrogenase |journal=European Journal of Biochemistry|date=FEB 1989|pages=355–359|pmid=2689175|accessdate=27 FEB 2013|volume=186|issue=1-2}}</ref>
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| This enzyme belongs to the family of [[oxidoreductase]]s, specifically those acting on the CH-OH group of donor with NAD<sup>+</sup> or NADP<sup>+</sup> as acceptor. The systematic name of this enzyme class is '''(R)-glycerate:NAD<sup>+</sup> oxidoreductase'''. Other names in common use include '''D-glycerate dehydrogenase''', and '''hydroxypyruvate reductase''' (due to the reversibility of the reaction). This enzyme participates in glycine, serine and [[threonine metabolism]] and [[glyoxylate and dicarboxylate metabolism]].
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| == Enzyme Structure ==
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| This class of enzyme is part of a larger [[protein family|superfamily]] of enzymes known as '''D-2-hydroxy-acid dehydrogenases'''.<ref name="pmid16756993">{{cite journal|last=Booth|first=Michael|coauthors=R. Connors, G. Rumsby, R. Leo Brady |title=Structural basis of substrate specificity in human glyoxylate reductase/hydroxypyruvate reductase |journal=Journal of Molecular Biology|date=18 May 2006|pages=178–189|pmid=16756993|accessdate=4 March 2013|doi=10.1016/j.jmb.2006.05.018|volume=360|issue=1}}</ref>
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| Many organisms from ''Hyphomicrobium methylovorum'' to humans have some form of the glycerate dehydrogenase protein. There are currently several [[tertiary structure|structures]] that have been solved for this class of enzyme including those for the two mentioned above with [[Protein Data Bank|PDB]] access code {{PDB link|1GDH}}, D-glycerate dehydrogenase, and the human homolog Glyoxylate Reductase/Hydroxypyruvate Reductase(GRHPR), {{PDB link|2WWR}}.
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| These studies have yielded a better understanding of the structure and function of these enzymes. It has been shown that that these proteins are homodimeric enzymes.<ref name="pmid8120891">{{cite journal|last=Goldberg|first=JD|coauthors=Yoshida, T; Brick, P|title=Crystal structure of a NAD-dependent D-glycerate dehydrogenase at 2.4 Å resolution |journal=Journal of Molecular Biology|date=Mar 4, 1994|year=1994|volume=236|issue=4|pages=1123–40|pmid=8120891|accessdate=1 March 2013}}</ref> This means that 2 identical proteins are linked forming one larger complex. The active sight is found in each subunit between the two distinct α/β/α globular domains, the substrate binding domain and the coenzyme binding domain.<ref name="pmid16756993"/> This coenzyme binding domain is slightly larger than the substrate binding domain and contains a NAD(P) [[Rossman fold]] along with the "''dimerisation loop''" which holds the two subunits of the homodimer together.<ref name="pmid16756993"/> In addition to linking the two proteins together, the "''dimerisation loop''" of each subunit protrudes into the active site of the other subunit increasing the specificity of the enzyme, by preventing the binding of pyruvate as a substrate. Hydroxypyruvate is still able to bind to the active site due to extra stabilization from hydrogen bonds with neighboring amino-acid residues.<ref name="pmid16756993"/>
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| ==Glyoxylate Reductase/Hydroxypyruvate Reductase==
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| ===Biological relevance===
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| '''Glyoxylate Reductase/Hydroxypyruvate Reductase''' (GRHPR) is the glycerate dehydrogenase found, predominantly in the liver, of humans encoded by the gene [[GRHPR]].<ref>{{cite journal|last=Cregeen|first=DP|coauthors=Williams, EL; Hulton, S; Rumsby, G|title=Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2 |journal=Human Mutation|date=December 2003|volume=22|issue=6|pages=497|pmid=14635115|doi=10.1002/humu.9200}}</ref> Under [[physiological condition]]s, the production of D-glycerate is favored over its consumption as a substrate. It can then be converted to 2-phosphoglycerate,<ref>{{cite journal|last=Liu|first=B|coauthors=Hong, Y; Wu, L; Li, Z; Ni, J; Sheng, D; Shen, Y|title=A unique highly thermostable 2-phosphoglycerate forming glycerate kinase from the hyperthermophilic archaeon ''Pyrococcus horikoshii'': gene cloning, expression and characterization |journal=Extremophiles : life under extreme conditions|date=September 2007|volume=11|issue=5|pages=733–9|pmid=17563835|doi=10.1007/s00792-007-0079-9}}</ref> which can then enter into [[glycolysis]], [[gluconeogenesis]], or the serine pathway.<ref>{{cite journal|last=Quayle|first=JR|title=Microbial assimilation of C1 compounds. The Thirteenth CIBA Medal Lecture.|journal=Biochemical Society transactions|date=February 1980|volume=8|issue=1|pages=1–10|pmid=6768606}}</ref><ref>{{cite journal|last=O'Connor|first=ML|coauthors=Hanson, RS|title=Serine transhydroxymethylase isoenzymes from a facultative methylotroph |journal=Journal of bacteriology|date=November 1975|volume=124|issue=2|pages=985–96|pmid=241747}}</ref>
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| As the name suggests, in addition to the glycerate dehydrogenase and hydroxypyruvate reductase activity, the protein also exhibits [[glyoxylate reductase]] activity.<ref name="pmid16756993"/> The ability of GRHPR to reduce [[glyoxylic acid|glyoxylate]] to [[glycolic acid|glycolate]] is found in other glycerate dehydrogenase homologs as well.<ref name="pmid2689175"/> This is important for the [[intracellular]] regulation of glyoxylate levels, which has important medical ramifications. As mentioned earlier, these enzymes have the ability to use either NADH or NADPH as the coenzyme. This gives them an advantage over other enzymes that can only use a single form of the coenzyme. '''[[Lactate dehydrogenase]](LDH)''' is one such enzyme that directly competes with GRHPR for substrates and converts glyoxylate to oxalate. However, due to the relatively large concentration of NADPH compared to NADH under normal cellular concentration, the GRHPR activity is greater than that of LDH so the production of glycolate is dominant.<ref name="pmid16756993"/>
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| ===Medical Relevance===
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| [[Primary hyperoxaluria]] is a condition that results in the over production of [[oxalic acid|oxalate]] which combines with calcium to generate calcium oxalate, the main component of kidney stones.<ref name="pmid22417769">{{cite journal|last=Mitsimponas|first=KT|coauthors=Wehrhan, T; Falk, S; Wehrhan, F; Neukam, FW; Schlegel, KA|title=Oral findings associated with primary hyperoxaluria type I |journal=Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery|date=December 2012|volume=40|issue=8|pages=e301-6|pmid=22417769|doi=10.1016/j.jcms.2012.01.009}}</ref><ref>{{cite web|title=Primary hyperoxaluria |url=http://ghr.nlm.nih.gov/condition/primary-hyperoxaluria|accessdate=4 March 2013}}</ref> Primary Hyperoxaluria type 2 is caused by any one of several mutations to the GRHPR gene and results in the accumulation of calcium oxalate in the kidneys, bones, and many other organs.<ref name="pmid22417769"/> The mutations to GRHPR prevent it from converting glyoxylate to glycolate, leading to a build-up of glyoxylate. This excess glyoxylate is then oxidized by [[lactate dehydrogenase]] to produce the oxalate that is characteristic of hyperoxaluria.
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| == References ==
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| {{reflist|1}}
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| * {{cite journal | author = Holzer H, Holldorf A | year = 1957 | title = [Isolation of D-glycerate dehydrogenase, some properties of the enzyme and its application to the enzymic-optic determination of hydroxypyruvate in presence of pyruvate] | language=German | journal = Biochem. Z. | volume = 329 | pages = 292–312 | pmid = 13522707 | issue = 4 }}
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| * {{cite journal | author = Stafford HA, Magaldi A, Vennesland B | year = 1954 | title = The enzymatic reduction of hydroxypyruvic acid to D-glyceric acid in higher plants | journal = J. Biol. Chem. | volume = 207 | pages = 621–9 | pmid = 13163046 | issue = 2 }}
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| * {{cite journal|last=Rumsby|first=G|coauthors=Pagon, RA; Bird, TD; Dolan, CR; Stephens, K; Adam, MP|title=Primary Hyperoxaluria Type 2 |year=1993|pmid=20301742}}
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| * {{cite journal|last=Cramer|first=SD|coauthors=Ferree, PM; Lin, K; Milliner, DS; Holmes, RP|title=The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II |journal=Human Molecular Genetics|date=October 1999|volume=8|issue=11|pages=2063–9|pmid=10484776|doi=10.1093/hmg/8.11.2063}}
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| [[Category:EC 1.1.1]]
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| [[Category:NADH-dependent enzymes]]
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| [[Category:Enzymes of known structure]]
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