View source for Phosphoglycerate dehydrogenase

{{Infobox_gene}}
{{enzyme
| Name = phosphoglycerate dehydrogenase
| EC_number = 1.1.1.95
| CAS_number =
| IUBMB_EC_number = 1/1/1/95
| GO_code =
| image =
| width =
| caption =
}}
In [[enzymology]], '''D-3-phosphoglycerate dehydrogenase''' (PHGDH) ({{EC number|1.1.1.95}}) is an [[enzyme]] that primarily [[catalysis|catalyzes]] the [[chemical reaction]]s

:3-phospho-D-glycerate + NAD<sup>+</sup> <math>\rightleftharpoons</math> 3-phosphonooxypyruvate + NADH + H<sup>+</sup>
:2-hydroxyglutarate + NAD<sup>+</sup> <math>\rightleftharpoons</math> 2-oxoglutarate + NADH + H<sup>+</sup>

Thus, in the first case, the two [[substrate (biochemistry)|substrates]] of this enzyme are [[3-phospho-D-glycerate]] and [[nicotinamide adenine dinucleotide|NAD<sup>+</sup>]], whereas its 3 [[product (chemistry)|products]] are [[3-phosphohydroxypyruvate]], [[nicotinamide adenine dinucleotide|NADH]], and [[hydrogen ion|H<sup>+</sup>]]; in the second case, the two substrates of this enzyme are [[2-hydroxyglutarate]] and NAD<sup>+</sup>, whereas its 3 products are [[2-oxoglutarate]], NADH, and [[hydrogen ion|H<sup>+</sup>]].

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 most widely studied variants of PHGDH are from the ''[[Escherichia coli|E. coli]]'' and ''[[Mycobacterium tuberculosis|M. tuberculosis]]'' genomes.<ref name="Grant_2012">{{cite journal | vauthors = Grant GA | title = Contrasting catalytic and allosteric mechanisms for phosphoglycerate dehydrogenases | journal = Archives of Biochemistry and Biophysics | volume = 519 | issue = 2 | pages = 175–85 | date = Mar 2012 | pmid = 22023909 | pmc = 3294004 | doi = 10.1016/j.abb.2011.10.005 }}</ref> In humans, this enzyme is encoded by the ''PHGDH'' [[gene]].<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=26227 | title = PHGDH phosphoglycerate dehydrogenase [Homo sapiens (human)] - Gene - NCBI | website = www.ncbi.nlm.nih.gov | access-date = 2016-03-01
}}</ref>

== Function ==

3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the [[committed step]] in the phosphorylated pathway of [[Serine|L-serine]] biosynthesis. It is also essential in [[cysteine]] and [[glycine]] synthesis, which lie further downstream.<ref>{{cite web | url = http://biocyc.org/META/NEW-IMAGE?type=PATHWAY&object=SERSYN-PWY
| title = MetaCyc L-serine biosynthesis | website = biocyc.org | access-date = 2016-03-01 }}</ref> This pathway represents the only way to synthesize serine in most organisms except plants, which uniquely possess multiple synthetic pathways. Nonetheless, the phosphorylated pathway that PHGDH participates in is still suspected to have an essential role in serine synthesis used in the developmental signaling of plants.<ref>{{cite journal | vauthors = Ros R, Muñoz-Bertomeu J, Krueger S | title = Serine in plants: biosynthesis, metabolism, and functions | journal = Trends in Plant Science | volume = 19 | issue = 9 | pages = 564–9 | date = Sep 2014 | pmid = 24999240 | doi = 10.1016/j.tplants.2014.06.003  }}</ref><ref>{{cite journal | vauthors = Ho CL, Noji M, Saito M, Saito K | title = Regulation of serine biosynthesis in Arabidopsis. Crucial role of plastidic 3-phosphoglycerate dehydrogenase in non-photosynthetic tissues | journal = The Journal of Biological Chemistry | volume = 274 | issue = 1 | pages = 397–402 | date = Jan 1999 | pmid = 9867856 | doi=10.1074/jbc.274.1.397}}</ref>

Because of serine and glycine’s role as [[neurotrophic factors]] in the developing brain, PHGDH has been shown to have high expression in [[Neuroglia|glial]] and [[astrocyte]] cells during neural development.<ref>{{cite journal | vauthors = Yamasaki M, Yamada K, Furuya S, Mitoma J, Hirabayashi Y, Watanabe M | title = 3-Phosphoglycerate dehydrogenase, a key enzyme for l-serine biosynthesis, is preferentially expressed in the radial glia/astrocyte lineage and olfactory ensheathing glia in the mouse brain | journal = The Journal of Neuroscience | volume = 21 | issue = 19 | pages = 7691–704 | date = Oct 2001 | pmid = 11567059 }}</ref>

== Mechanism and regulation ==

3-phosphoglycerate dehydrogenase works via an induced fit mechanism to catalyze the transfer of a [[hydride]] from the substrate to NAD+, a required [[Cofactor (biochemistry)|cofactor]]. In its active conformation, the enzyme’s active site has multiple cationic residues that likely stabilize the transition state of the reaction between the negatively charged substrate and NAD<sup>+</sup>. The positioning is such that the substrate’s alpha carbon and the C4 of the nicotinamide ring are brought into a proximity that facilitates the hydride transfer producing NADH and the oxidized substrate.<ref name="Grant_2012" /><ref name="Grant_1999">{{cite journal | vauthors = Grant GA, Kim SJ, Xu XL, Hu Z | title = The contribution of adjacent subunits to the active sites of D-3-phosphoglycerate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 9 | pages = 5357–61 | date = Feb 1999 | pmid = 10026144 | doi=10.1074/jbc.274.9.5357}}</ref>

[[File:PHGDH Active Site.png|thumb|Active site of human PHGDH. Key residues (two Arg and one His) and substrates shown. The 4.2 Å distance is between the carbons undergoing hydride transfer. From 2G76 rendering of PHGDH crystallized with NAD<sup>+</sup> and D-malate.]]

PHGDH is [[Allosteric regulation|allosterically]] regulated by its downstream product, L-serine. This feedback inhibition is understandable considering that 3-phosphoglycerate is an intermediate in the [[Glycolysis|glycolytic]] pathway. Given that PHGDH represents the committed step in the production of serine in the cell, flux through the pathway must be carefully controlled.

L-serine binding has been shown to exhibit [[Cooperativity|cooperative]] behavior. Mutants that decreased this cooperativity also increased in sensitivity to serine’s allosteric inhibition, suggesting a separation of the chemical mechanisms that result in allosteric binding cooperativity and active site inhibition.<ref>{{cite journal | vauthors = Grant GA, Hu Z, Xu XL | title = Specific interactions at the regulatory domain-substrate binding domain interface influence the cooperativity of inhibition and effector binding in Escherichia coli D-3-phosphoglycerate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 276 | issue = 2 | pages = 1078–83 | date = Jan 2001 | pmid = 11050089 | doi = 10.1074/jbc.M007512200 }}</ref> The mechanism of inhibition is Vmax type, indicating that serine affects the reaction rate rather than the binding affinity of the active site.<ref name="Grant_1999" /><ref name="Grant_1996">{{cite journal | vauthors = Grant GA, Schuller DJ, Banaszak LJ | title = A model for the regulation of D-3-phosphoglycerate dehydrogenase, a Vmax-type allosteric enzyme | journal = Protein Science | volume = 5 | issue = 1 | pages = 34–41 | date = Jan 1996 | pmid = 8771194 | pmc = 2143248 | doi = 10.1002/pro.5560050105 }}</ref>

Although L-serine’s allosteric effects are usually the focus of regulatory investigation, it has been noted that in some variants of the enzyme, 3-phosphoglycerate dehydrogenase is inhibited at separate positively charged allosteric site by high concentrations of its own substrate.<ref name="Grant_2012" /><ref name="Burton_2007">{{cite journal | vauthors = Burton RL, Chen S, Xu XL, Grant GA | title = A novel mechanism for substrate inhibition in Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 282 | issue = 43 | pages = 31517–24 | date = Oct 2007 | pmid = 17761677 | doi = 10.1074/jbc.M704032200 }}</ref>

== Structure ==

3-Phosphoglycerate dehydrogenase is a [[tetramer]], composed of four identical, asymmetric subunits. At any time, only a maximum of two adjacent subunits present a catalytically active site; the other two are forced into an inactive conformation. This results in half-of-the-sites activity with regard to both active and allosteric sites, meaning that only the two sites of the active subunits must be bound for essentially maximal effect with regard to catalysis and inhibition respectively.<ref>{{cite journal | vauthors = Grant GA, Xu XL, Hu Z | title = Quantitative relationships of site to site interaction in Escherichia coli D-3-phosphoglycerate dehydrogenase revealed by asymmetric hybrid tetramers | journal = The Journal of Biological Chemistry | volume = 279 | issue = 14 | pages = 13452–60 | date = Apr 2004 | pmid = 14718528 | doi = 10.1074/jbc.M313593200 }}</ref> There is some evidence that further inhibition occurs with the binding of the third and fourth serine molecules, but it is relatively minimal.<ref name="Grant_1996"/>

The subunits from the ''E. coli'' PHGDH have three distinct domains, whereas those from ''M. tuberculosis'' have four. It is noted that the human enzyme more closely resembles that of ''M. tuberculosis'', including the site for allosteric substrate inhibition. Concretely, three general types of PHGDH have been proposed: Type I, II, and III. Type III has two distinct domains, lacks both allosteric sites, and is found in various unicellular organisms. Type II has serine binding sites and encompasses the well-studied ''E. coli'' PHGDH. Type I possesses both the serine and substrate allosteric binding sites and encompasses ''M. tuberculosis'' and mammalian PHGDHs.<ref name="Grant_2012" />

The regulation of catalytic activity is thought to be a result of the movement of rigid domains about flexible “hinges.” When the substrate binds to the open active site, the hinge rotates and closes the cleft. Allosteric inhibition thus likely works by locking the hinge in a state that produces the open active site cleft.<ref name="Grant_1996" /><ref>{{cite journal | vauthors = Al-Rabiee R, Lee EJ, Grant GA | title = The mechanism of velocity modulated allosteric regulation in D-3-phosphoglycerate dehydrogenase. Cross-linking adjacent regulatory domains with engineered disulfides mimics effector binding | journal = The Journal of Biological Chemistry | volume = 271 | issue = 22 | pages = 13013–7 | date = May 1996 | pmid = 8662776 }}</ref>

[[File:Inhibited PHGDH.png|thumb|Crystal structure of inhibited PHGDH from M. tuberculosis due to allosterically bound serine. From 3DC2 rendering.]]

The variant from ''M. tuberculosis'' also exhibits an uncommon dual [[pH]] optimum for catalytic activity.<ref name="Burton_2007" />

== Evolution ==
3-Phosphoglycerate dehydrogenase possesses less than 20% homology to other NAD-dependent oxidoreductases and exhibits significant variance between species. There does appear to be conservation in specific binding domain residues, but there is still some variation in the positively charged active site residues between variants. For example, Type III PHGDH enzymes can be broken down into two subclasses where the key [[histidine]] residue is replaced with a [[lysine]] residue.<ref name="Grant_2012" /><ref>{{cite journal | vauthors = Tobey KL, Grant GA | title = The nucleotide sequence of the serA gene of Escherichia coli and the amino acid sequence of the encoded protein, D-3-phosphoglycerate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 261 | issue = 26 | pages = 12179–83 | date = Sep 1986 | pmid = 3017965 }}</ref>

== Disease relevance ==

Homozygous or compound heterozygous mutations in 3-phosphoglycerate dehydrogenase cause [[Neu-Laxova syndrome]]<ref>{{cite journal | vauthors = Shaheen R, Rahbeeni Z, Alhashem A, Faqeih E, Zhao Q, Xiong Y, Almoisheer A, Al-Qattan SM, Almadani HA, Al-Onazi N, Al-Baqawi BS, Saleh MA, Alkuraya FS | title = Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH | journal = American Journal of Human Genetics | volume = 94 | issue = 6 | pages = 898–904 | date = Jun 2014 | pmid = 24836451 | pmc = 4121479 | doi = 10.1016/j.ajhg.2014.04.015 }}</ref><ref>{{cite journal | vauthors = Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M | title = Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway | journal = American Journal of Human Genetics | volume = 95 | issue = 3 | pages = 285–93 | date = Sep 2014 | pmid = 25152457 | pmc = 4157144 | doi = 10.1016/j.ajhg.2014.07.012 }}</ref> and phosphoglycerate dehydrogenase deficiency.<ref>{{cite journal | vauthors = Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E | title = 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis | journal = Archives of Disease in Childhood | volume = 74 | issue = 6 | pages = 542–5 | date = Jun 1996 | pmid = 8758134 | pmc = 1511571 | doi=10.1136/adc.74.6.542}}</ref> In addition significantly shortening lifespan, PHGDH deficiencies are known to cause [[Microcephaly|congenital microcephaly]], [[psychomotor retardation]], and intractable [[Epileptic seizure|seizures]] in both humans and rats, presumably due to the essential signaling within the nervous system that serine, glycine, and other downstream molecules are intimately involved with. Treatment typically involves oral supplementation of serine and glycine and has been shown most effective when started ''in utero'' via oral ingestion by the mother.<ref>{{cite journal | vauthors = de Koning TJ, Duran M, Dorland L, Gooskens R, Van Schaftingen E, Jaeken J, Blau N, Berger R, Poll-The BT | title = Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency | journal = Annals of Neurology | volume = 44 | issue = 2 | pages = 261–5 | date = Aug 1998 | pmid = 9708551 | doi = 10.1002/ana.410440219 }}</ref><ref>{{cite journal | vauthors = de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I, Berger R | title = Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency | journal = Lancet | volume = 364 | issue = 9452 | pages = 2221–2 | date = 2004-12-18 | pmid = 15610810 | doi = 10.1016/S0140-6736(04)17596-X }}</ref>

[[Mutation]]s that result in increased PHGDH activity are also associated with increased risk of [[Carcinogenesis|oncogenesis]], including certain [[breast cancer]]s.<ref>{{cite journal | vauthors = Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM | title = Functional genomics reveal that the serine synthesis pathway is essential in breast cancer | journal = Nature | volume = 476 | issue = 7360 | pages = 346–50 | date = Aug 2011 | pmid = 21760589 | pmc = 3353325 | doi = 10.1038/nature10350 }}</ref> This finding suggests that pathways providing an outlet for diverting carbon out of glycolysis may be beneficial for rapid cell growth.<ref>{{cite journal | vauthors = Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG | title = Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis | journal = Nature Genetics | volume = 43 | issue = 9 | pages = 869–74 | date = Sep 2011 | pmid = 21804546 | pmc = 3677549 | doi = 10.1038/ng.890 | url = http://dspace.mit.edu/bitstream/1721.1/76302/1/PHGDH_NatGen_FINAL2.0.pdf }}</ref>

It has been reported that PHGDH can also catalyze the conversion of [[Alpha-Ketoglutaric acid|alpha-ketoglutarate]] to [[2-Hydroxyglutaric acid|2-hydroxyglutaric acid]] in certain variants. Thus, a mutation in the enzyme is hypothesized to contribute to [[2-Hydroxyglutaric aciduria|2-hydroxyglutaric aciduria]] in humans, although there is debate as to whether or not this catalysis is shared by human PHGDH.<ref name="Grant_2012" /><ref>{{cite journal | vauthors = Zhao G, Winkler ME | title = A novel alpha-ketoglutarate reductase activity of the serA-encoded 3-phosphoglycerate dehydrogenase of Escherichia coli K-12 and its possible implications for human 2-hydroxyglutaric aciduria | journal = Journal of Bacteriology | volume = 178 | issue = 1 | pages = 232–9 | date = Jan 1996 | pmid = 8550422 | pmc = 177644 }}</ref>

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Tsang HT, Connell JW, Brown SE, Thompson A, Reid E, Sanderson CM | title = A systematic analysis of human CHMP protein interactions: additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex | journal = Genomics | volume = 88 | issue = 3 | pages = 333–46 | date = Sep 2006 | pmid = 16730941 | doi = 10.1016/j.ygeno.2006.04.003 }}
* {{cite journal | vauthors = Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, Eizirik DL, She JX, Wang CY | title = Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress | journal = Biochemical and Biophysical Research Communications | volume = 337 | issue = 4 | pages = 1308–18 | date = Dec 2005 | pmid = 16236267 | doi = 10.1016/j.bbrc.2005.09.191 }}
* {{cite journal | vauthors = Pind S, Slominski E, Mauthe J, Pearlman K, Swoboda KJ, Wilkins JA, Sauder P, Natowicz MR | title = V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme | journal = The Journal of Biological Chemistry | volume = 277 | issue = 9 | pages = 7136–43 | date = Mar 2002 | pmid = 11751922 | doi = 10.1074/jbc.M111419200 }}
* {{cite journal | vauthors = Klomp LW, de Koning TJ, Malingré HE, van Beurden EA, Brink M, Opdam FL, Duran M, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van den Berg IE, Berger R | title = Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency--a neurometabolic disorder associated with reduced L-serine biosynthesis | journal = American Journal of Human Genetics | volume = 67 | issue = 6 | pages = 1389–99 | date = Dec 2000 | pmid = 11055895 | pmc = 1287916 | doi = 10.1086/316886 }}
* {{cite journal | vauthors = Pineda M, Vilaseca MA, Artuch R, Santos S, García González MM, Aracil A, Van Schaftingen E, Jaeken J | title = 3-phosphoglycerate dehydrogenase deficiency in a patient with West syndrome | journal = Developmental Medicine and Child Neurology | volume = 42 | issue = 9 | pages = 629–33 | date = Sep 2000 | pmid = 11034457 | doi = 10.1017/S0012162200001171 }}
* {{cite journal | vauthors = Baek JY, Jun DY, Taub D, Kim YH | title = Assignment of human 3-phosphoglycerate dehydrogenase (PHGDH) to human chromosome band 1p12 by fluorescence in situ hybridization | journal = Cytogenetics and Cell Genetics | volume = 89 | issue = 1-2 | pages = 6–7 | year = 2000 | pmid = 10894924 | doi = 10.1159/000015577 }}
* {{cite journal | vauthors = Cho HM, Jun DY, Bae MA, Ahn JD, Kim YH | title = Nucleotide sequence and differential expression of the human 3-phosphoglycerate dehydrogenase gene | journal = Gene | volume = 245 | issue = 1 | pages = 193–201 | date = Mar 2000 | pmid = 10713460 | doi = 10.1016/S0378-1119(00)00009-3 }}
* {{cite journal | vauthors = Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E | title = 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis | journal = Archives of Disease in Childhood | volume = 74 | issue = 6 | pages = 542–5 | date = Jun 1996 | pmid = 8758134 | pmc = 1511571 | doi = 10.1136/adc.74.6.542 }}
{{refend}}
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[[Category:EC 1.1.1]]
[[Category:NADH-dependent enzymes]]
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