Phosphoglycerate dehydrogenase

Last updated

PHGDH
Protein PHGDH PDB 2g76.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PHGDH , 3-PGDH, 3PGDH, HEL-S-113, NLS, PDG, PGAD, PGD, PGDH, PHGDHD, SERA, NLS1, Phosphoglycerate dehydrogenase
External IDs OMIM: 606879; MGI: 1355330; HomoloGene: 39318; GeneCards: PHGDH; OMA:PHGDH - orthologs
Orthologs
SpeciesHumanMouse
Entrez

26227

236539

Ensembl

ENSG00000092621

ENSMUSG00000053398

UniProt

O43175

Q61753

RefSeq (mRNA)

NM_006623
NM_032692

NM_016966

RefSeq (protein)

NP_006614

NP_058662

Location (UCSC) Chr 1: 119.65 – 119.74 Mb Chr 3: 98.22 – 98.25 Mb
PubMed search [3] [4]
Wikidata
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phosphoglycerate dehydrogenase
Identifiers
EC no. 1.1.1.95
Databases
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BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
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PMC articles
PubMed articles
NCBI proteins

Phosphoglycerate dehydrogenase (PHGDH) is an enzyme that catalyzes the chemical reactions

Contents

3-phospho-D-glycerate + NAD+ 3-phosphonooxypyruvate + NADH + H+
2-hydroxyglutarate + NAD+ 2-oxoglutarate + NADH + H+

The two substrates of this enzyme are 3-phospho-D-glycerate and NAD+, whereas its 3 products are 3-phosphohydroxypyruvate, NADH, and H+

It is also possible that two substrates of this enzyme are 2-hydroxyglutarate and NAD+, whereas its 3 products are 2-oxoglutarate, NADH, and H+.

As of 2012, the most widely studied variants of PHGDH are from the E. coli and M. tuberculosis genomes. [5] In humans, this enzyme is encoded by the PHGDH gene. [6]

Function

3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the committed step in the phosphorylated pathway of L-serine biosynthesis. It is also essential in cysteine and glycine synthesis, which lie further downstream. [7] 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. [8] [9]

Because of serine and glycine's role as neurotrophic factors in the developing brain, PHGDH has been shown to have high expression in glial and astrocyte cells during neural development. [10]

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. 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+. 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. [5] [11]

Active site of human PHGDH. Key residues (two Arg and one His) and substrates shown. The 4.2 A distance is between the carbons undergoing hydride transfer. From 2G76 rendering of PHGDH crystallized with NAD and D-malate. PHGDH Active Site.png
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 and D-malate.

PHGDH is allosterically regulated by its downstream product, L-serine. This feedback inhibition is understandable considering that 3-phosphoglycerate is an intermediate in the 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 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. [12] The mechanism of inhibition is Vmax type, indicating that serine affects the reaction rate rather than the binding affinity of the active site. [11] [13]

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. [5] [14]

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. [15] There is some evidence that further inhibition occurs with the binding of the third and fourth serine molecules, but it is relatively minimal. [13]

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. [5]

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. [13] [16]

Crystal structure of inhibited PHGDH from M. tuberculosis due to allosterically bound serine. From 3DC2 rendering. Inhibited PHGDH.png
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. [14]

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. [5] [17]

Disease relevance

Homozygous or compound heterozygous mutations in 3-phosphoglycerate dehydrogenase cause Neu–Laxova syndrome [18] [19] and phosphoglycerate dehydrogenase deficiency. [20] In addition significantly shortening lifespan, PHGDH deficiencies are known to cause congenital microcephaly, psychomotor retardation, and intractable 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. [21] [22]

Mutations that result in increased PHGDH activity are also associated with increased risk of oncogenesis, including certain breast cancers. [23] This finding suggests that pathways providing an outlet for diverting carbon out of glycolysis may be beneficial for rapid cell growth. [24]

It has been reported that PHGDH can also catalyze the conversion of alpha-ketoglutarate to 2-Hydroxyglutaric acid in certain variants. Thus, a mutation in the enzyme is hypothesized to contribute to 2-Hydroxyglutaric aciduria in humans, although there is debate as to whether or not this catalysis is shared by human PHGDH. [5] [25]

Research results suggest that PHGDH could serve as a blood biomarker of Alzheimer's disease. [26]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

<span class="mw-page-title-main">Pyruvate dehydrogenase complex</span> Three-enzyme complex

Pyruvate dehydrogenase complex (PDC) is a complex of three enzymes that converts pyruvate into acetyl-CoA by a process called pyruvate decarboxylation. Acetyl-CoA may then be used in the citric acid cycle to carry out cellular respiration, and this complex links the glycolysis metabolic pathway to the citric acid cycle. Pyruvate decarboxylation is also known as the "pyruvate dehydrogenase reaction" because it also involves the oxidation of pyruvate.

<span class="mw-page-title-main">Glutamate dehydrogenase</span> Hexameric enzyme

Glutamate dehydrogenase is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typically, the α-ketoglutarate to glutamate reaction does not occur in mammals, as glutamate dehydrogenase equilibrium favours the production of ammonia and α-ketoglutarate. Glutamate dehydrogenase also has a very low affinity for ammonia, and therefore toxic levels of ammonia would have to be present in the body for the reverse reaction to proceed. However, in brain, the NAD+/NADH ratio in brain mitochondria encourages oxidative deamination. In bacteria, the ammonia is assimilated to amino acids via glutamate and aminotransferases. In plants, the enzyme can work in either direction depending on environment and stress. Transgenic plants expressing microbial GLDHs are improved in tolerance to herbicide, water deficit, and pathogen infections. They are more nutritionally valuable.

<span class="mw-page-title-main">Malate dehydrogenase</span> Class of enzymes

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

In molecular biology, biosynthesis is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products in living organisms. In biosynthesis, simple compounds are modified, converted into other compounds, or joined to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism.

<span class="mw-page-title-main">Isocitrate dehydrogenase</span> Class of enzymes

Isocitrate dehydrogenase (IDH) (EC 1.1.1.42) and (EC 1.1.1.41) is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a secondary alcohol) to oxalosuccinate (a ketone), followed by the decarboxylation of the carboxyl group beta to the ketone, forming alpha-ketoglutarate. In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle while converting NAD+ to NADH in the mitochondria. The isoforms IDH1 and IDH2 catalyze the same reaction outside the context of the citric acid cycle and use NADP+ as a cofactor instead of NAD+. They localize to the cytosol as well as the mitochondrion and peroxisome.

The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid biosynthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids.

<span class="mw-page-title-main">Shikimate dehydrogenase</span> Enzyme involved in amino acid biosynthesis

In enzymology, a shikimate dehydrogenase (EC 1.1.1.25) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Homoserine dehydrogenase</span> Enzyme

In enzymology, a homoserine dehydrogenase (EC 1.1.1.3) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Glycerate dehydrogenase</span>

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In enzymology, a 4-phosphoerythronate dehydogenase (EC 1.1.1.290) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">L-threonine 3-dehydrogenase</span> Class of enzymes

In enzymology, a L-threonine 3-dehydrogenase (EC 1.1.1.103) is an enzyme that catalyzes the chemical reaction

Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP<sup>+</sup>) Enzyme

Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) (EC 1.1.1.40) or NADP-malic enzyme (NADP-ME) is an enzyme that catalyzes the chemical reaction in the presence of a bivalent metal ion:

<span class="mw-page-title-main">UDP-glucose 4-epimerase</span> Class of enzymes

The enzyme UDP-glucose 4-epimerase, also known as UDP-galactose 4-epimerase or GALE, is a homodimeric epimerase found in bacterial, fungal, plant, and mammalian cells. This enzyme performs the final step in the Leloir pathway of galactose metabolism, catalyzing the reversible conversion of UDP-galactose to UDP-glucose. GALE tightly binds nicotinamide adenine dinucleotide (NAD+), a co-factor required for catalytic activity.

<span class="mw-page-title-main">Threonine ammonia-lyase</span>

Threonine ammonia-lyase (EC 4.3.1.19, systematic name L-threonine ammonia-lyase (2-oxobutanoate-forming), also commonly referred to as threonine deaminase or threonine dehydratase, is an enzyme responsible for catalyzing the conversion of L-threonine into α-ketobutyrate and ammonia:

<span class="mw-page-title-main">IDH3A</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit alpha, mitochondrial (IDH3α) is an enzyme that in humans is encoded by the IDH3A gene.

<span class="mw-page-title-main">IDH3B</span> Protein-coding gene in the species Homo sapiens

Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial is an enzyme that in humans is encoded by the IDH3B gene.

<span class="mw-page-title-main">Inosine-5′-monophosphate dehydrogenase</span> Class of enzymes

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a purine biosynthetic enzyme that catalyzes the nicotinamide adenine dinucleotide (NAD+)-dependent oxidation of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), the first committed and rate-limiting step towards the de novo biosynthesis of guanine nucleotides from IMP. IMPDH is a regulator of the intracellular guanine nucleotide pool, and is therefore important for DNA and RNA synthesis, signal transduction, energy transfer, glycoprotein synthesis, as well as other process that are involved in cellular proliferation.

<span class="mw-page-title-main">D-glycerate dehydrogenase deficiency</span> Rare autosomal recessive human diseases

D-glycerate dehydrogenase deficiency is a rare autosomal metabolic disease where the young patient is unable to produce an enzyme necessary to convert 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the only way for humans to synthesize serine.This disorder is called Neu–Laxova syndrome in neonates.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000092621 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000053398 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 Grant GA (March 2012). "Contrasting catalytic and allosteric mechanisms for phosphoglycerate dehydrogenases". Archives of Biochemistry and Biophysics. 519 (2): 175–85. doi:10.1016/j.abb.2011.10.005. PMC   3294004 . PMID   22023909.
  6. ↑ "PHGDH phosphoglycerate dehydrogenase [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 1 March 2016.
  7. ↑ "MetaCyc L-serine biosynthesis". biocyc.org. Retrieved 1 March 2016.
  8. ↑ Ros R, Muñoz-Bertomeu J, Krueger S (September 2014). "Serine in plants: biosynthesis, metabolism, and functions". Trends in Plant Science. 19 (9): 564–9. doi:10.1016/j.tplants.2014.06.003. PMID   24999240. S2CID   19690197.
  9. ↑ Ho CL, Noji M, Saito M, Saito K (January 1999). "Regulation of serine biosynthesis in Arabidopsis. Crucial role of plastidic 3-phosphoglycerate dehydrogenase in non-photosynthetic tissues". The Journal of Biological Chemistry. 274 (1): 397–402. doi: 10.1074/jbc.274.1.397 . PMID   9867856.
  10. ↑ Yamasaki M, Yamada K, Furuya S, Mitoma J, Hirabayashi Y, Watanabe M (October 2001). "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". The Journal of Neuroscience. 21 (19): 7691–704. doi: 10.1523/JNEUROSCI.21-19-07691.2001 . PMC   6762884 . PMID   11567059. S2CID   3547638.
  11. 1 2 Grant GA, Kim SJ, Xu XL, Hu Z (February 1999). "The contribution of adjacent subunits to the active sites of D-3-phosphoglycerate dehydrogenase". The Journal of Biological Chemistry. 274 (9): 5357–61. doi: 10.1074/jbc.274.9.5357 . PMID   10026144.
  12. ↑ Grant GA, Hu Z, Xu XL (January 2001). "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". The Journal of Biological Chemistry. 276 (2): 1078–83. doi: 10.1074/jbc.M007512200 . PMID   11050089.
  13. 1 2 3 Grant GA, Schuller DJ, Banaszak LJ (January 1996). "A model for the regulation of D-3-phosphoglycerate dehydrogenase, a Vmax-type allosteric enzyme". Protein Science. 5 (1): 34–41. doi:10.1002/pro.5560050105. PMC   2143248 . PMID   8771194.
  14. 1 2 Burton RL, Chen S, Xu XL, Grant GA (October 2007). "A novel mechanism for substrate inhibition in Mycobacterium tuberculosis D-3-phosphoglycerate dehydrogenase". The Journal of Biological Chemistry. 282 (43): 31517–24. doi: 10.1074/jbc.M704032200 . PMID   17761677.
  15. ↑ Grant GA, Xu XL, Hu Z (April 2004). "Quantitative relationships of site to site interaction in Escherichia coli D-3-phosphoglycerate dehydrogenase revealed by asymmetric hybrid tetramers". The Journal of Biological Chemistry. 279 (14): 13452–60. doi: 10.1074/jbc.M313593200 . PMID   14718528.
  16. ↑ Al-Rabiee R, Lee EJ, Grant GA (May 1996). "The mechanism of velocity modulated allosteric regulation in D-3-phosphoglycerate dehydrogenase. Cross-linking adjacent regulatory domains with engineered disulfides mimics effector binding". The Journal of Biological Chemistry. 271 (22): 13013–7. doi: 10.1074/jbc.271.22.13013 . PMID   8662776. S2CID   28327405.
  17. ↑ Tobey KL, Grant GA (September 1986). "The nucleotide sequence of the serA gene of Escherichia coli and the amino acid sequence of the encoded protein, D-3-phosphoglycerate dehydrogenase". The Journal of Biological Chemistry. 261 (26): 12179–83. doi: 10.1016/S0021-9258(18)67220-5 . PMID   3017965.
  18. ↑ 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 (June 2014). "Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH". American Journal of Human Genetics. 94 (6): 898–904. doi:10.1016/j.ajhg.2014.04.015. PMC   4121479 . PMID   24836451.
  19. ↑ 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 (September 2014). "Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway". American Journal of Human Genetics. 95 (3): 285–93. doi:10.1016/j.ajhg.2014.07.012. PMC   4157144 . PMID   25152457.
  20. ↑ Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E (June 1996). "3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis". Archives of Disease in Childhood. 74 (6): 542–5. doi:10.1136/adc.74.6.542. PMC   1511571 . PMID   8758134.
  21. ↑ de Koning TJ, Duran M, Dorland L, Gooskens R, Van Schaftingen E, Jaeken J, Blau N, Berger R, Poll-The BT (August 1998). "Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency". Annals of Neurology. 44 (2): 261–5. doi: 10.1002/ana.410440219 . PMID   9708551. S2CID   46565109.
  22. ↑ de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I, Berger R (18 December 2004). "Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency". Lancet. 364 (9452): 2221–2. doi:10.1016/S0140-6736(04)17596-X. PMID   15610810. S2CID   40121728.
  23. ↑ 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 (August 2011). "Functional genomics reveal that the serine synthesis pathway is essential in breast cancer". Nature. 476 (7360): 346–50. Bibcode:2011Natur.476..346P. doi:10.1038/nature10350. PMC   3353325 . PMID   21760589.
  24. ↑ 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 (September 2011). "Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis" (PDF). Nature Genetics. 43 (9): 869–74. doi:10.1038/ng.890. PMC   3677549 . PMID   21804546.
  25. ↑ Zhao G, Winkler ME (January 1996). "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 of Bacteriology. 178 (1): 232–9. doi:10.1128/JB.178.1.232-239.1996. PMC   177644 . PMID   8550422.
  26. ↑ Chen X, Calandrelli R, Girardini J, Yan Z, Tan Z, Xu X, Hiniker A, Zhong S (May 2022). "PHGDH expression increases with progression of Alzheimer's disease pathology and symptoms". Cell Metabolism. 34 (5): 651–653. doi:10.1016/j.cmet.2022.02.008. PMC   9531314 . PMID   35508105.
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