Glycerol-3-phosphate dehydrogenase

Glycerol-3-phosphate dehydrogenase (GPDH) is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate.^[2]

Glycerol-3-phosphate dehydrogenase serves as a major link between carbohydrate metabolism and lipid metabolism. It is also a major contributor of electrons to the electron transport chain in the mitochondria.

Older terms for glycerol-3-phosphate dehydrogenase include alpha glycerol-3-phosphate dehydrogenase (alphaGPDH) and glycerolphosphate dehydrogenase (GPDH). However, glycerol-3-phosphate dehydrogenase is not the same as glyceraldehyde 3-phosphate dehydrogenase (GAPDH), whose substrate is an aldehyde not an alcohol.

Metabolic function

GPDH plays a major role in lipid biosynthesis. Through the reduction of dihydroxyacetone phosphate into glycerol 3-phosphate, GPDH allows the prompt dephosphorylation of glycerol 3-phosphate into glycerol.^[3] Additionally, GPDH is responsible for maintaining the redox potential across the inner mitochondrial membrane in glycolysis.^[3]

Fig. 1. Schematic overview of fermentative and oxidative glucose metabolism of Saccharomyces cerevisiae. (A) upper part of glycolysis, which includes two sugar phosphorylation reactions. (B) fructose-1,6-bisphosphate aldolase, splitting the C6-molecule into two triose phosphates (C) triosephosphate isomerase, interconverting DHAP and GAP. (D) glycerol pathway reducing DHAP to glycerol-3-phosphate (G3P) by G3P dehydrogenase, followed by dephosphorylation to glycerol by G3Pase. (E) The lower part of glycolysis converts GAP to pyruvate while generating 1 NADH and 2 ATP via a series of 5 enzymes. (F) Alcoholic fermentation; decarboxylation of pyruvate by pyruvate decarboxylase, followed by reduction of acetaldehyde to ethanol. (G) mitochondrial pyruvate-dehydrogenase converts pyruvate to acetyl-CoA, which enters the tricarboxylic acid cycle. (H) external mitochondrial NADH dehydrogenases. (I) mitochondrial G3P dehydrogenase. Electrons of these three dehydrogenases enter the respiratory chain at the level of the quinol pool (Q). (J) internal mitochondrial NADH dehydrogenase. (K) ATP synthase. (L) generalized scheme of NADH shuttle. (M) formate oxidation by formate dehydrogenase.^[4]

Reaction

The NAD+/NADH coenzyme couple act as an electron reservoir for metabolic redox reactions, carrying electrons from one reaction to another.^[5] Most of these metabolism reactions occur in the mitochondria. To regenerate NAD+ for further use, NADH pools in the cytosol must be reoxidized. Since the mitochondrial inner membrane is impermeable to both NADH and NAD+, these cannot be freely exchanged between the cytosol and mitochondrial matrix.^[4]

One way to shuttle this reducing equivalent across the membrane is through the Glycerol-3-phosphate shuttle, which employs the two forms of GPDH:

Cytosolic GPDH, or GPD1 is located in the mitochondrial inner-membrane space or cytosol, and catalyzes the reduction of dihydroxyacetone phosphate into glycerol-3-phosphate.
In conjunction, Mitochondrial GPDH, or GPD2 is embedded on the outer surface of the inner mitochondrial membrane, overlooking the cytosol, and catalyzes the oxidation of glycerol-3-phosphate to dihydroxyacetone phosphate.^[6]

The reactions catalyzed by cytosolic (soluble) and mitochondrial GPDH are as follows:

Coupled reactions catalyzed by the cytosolic (GPDH-C) and mitochondrial (GPDH-M) forms of glycerol 3-phosphate dehydrogenase.^[7] GPDH-C and GPDH-M use NADH and quinol (QH) as an electron donors respectively. GPDH-M in addition uses FAD as a co-factor.

Variants

There are two forms of GPDH:

Enzyme			Protein			Gene
EC number	Name	Donor / Acceptor	Name	Subcellular location	Abbreviation	Name	Symbol
1.1.1.8	glycerol-3-phosphate dehydrogenase	NADH / NAD⁺	Glycerol-3-phosphate dehydrogenase [NAD⁺]	cytoplasmic	GPDH-C	glycerol-3-phosphate dehydrogenase 1 (soluble)	GPD1
1.1.5.3	glycerol-3-phosphate dehydrogenase	quinol / quinone	Glycerol-3-phosphate dehydrogenase	mitochondrial	GPDH-M	glycerol-3-phosphate dehydrogenase 2 (mitochondrial)	GPD2

The following human genes encode proteins with GPDH enzymatic activity:

glycerol-3-phosphate dehydrogenase 1 (soluble)
Identifiers
Symbol	GPD1
Entrez	2819
HUGO	4455
OMIM	138420
RefSeq	NM_005276
UniProt	P21695
Other data
EC number	1.1.1.8
Locus	Chr. 12 q12-q13

glycerol-3-phosphate dehydrogenase 2 (mitochondrial)
Identifiers
Symbol	GPD2
Entrez	2820
HUGO	4456
OMIM	138430
RefSeq	NM_000408
UniProt	P43304
Other data
EC number	1.1.5.3
Locus	Chr. 2 q24.1

GPD1

Cytosolic Glycerol-3-phosphate dehydrogenase (GPD1), is an NAD+-dependent enzyme^[8] that reduces dihydroxyacetone phosphate to glycerol-3-phosphate. Simultaneously, NADH is oxidized to NAD+ in the following reaction:

GPD1 Reaction Mechanism

As a result, NAD+ is regenerated for further metabolic activity.

GPD1 consists of two subunits,^[9] and reacts with dihydroxyacetone phosphate and NAD+ though the following interaction:

Figure 4. The putative active site. The phosphate group of DHAP is half-encircled by the side-chain of Arg269, and interacts with Arg269 and Gly268 directly by hydrogen bonds (not shown). The conserved residues Lys204, Asn205, Asp260 and Thr264 form a stable hydrogen bonding network. The other hydrogen bonding network includes residues Lys120 and Asp260, as well as an ordered water molecule (with a B-factor of 16.4 Å2), which hydrogen bonds to Gly149 and Asn151 (not shown). In these two electrostatic networks, only the ε-NH₃⁺ group of Lys204 is the nearest to the C2 atom of DHAP (3.4 Å).^[1]

GPD2

Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2), catalyzes the irreversible oxidation of glycerol-3-phosphate to dihydroxyacetone phosphate and concomitantly transfers two electrons from FAD to the electron transport chain. GPD2 consists of 4 identical subunits.^[10]

GPD2 Reaction Mechanism

Response to environmental stresses

Studies indicate that GPDH is mostly unaffected by pH changes: neither GPD1 or GPD2 is favored under certain pH conditions.
At high salt concentrations (E.g. NaCl), GPD1 activity is enhanced over GPD2, since an increase in the salinity of the medium leads to an accumulation of glycerol in response.
Changes in temperature do not appear to favor neither GPD1 nor GPD2.^[11]

Glycerol-3-phosphate shuttle

Main article: Glycerol phosphate shuttle

The cytosolic together with the mitochondrial glycerol-3-phosphate dehydrogenase work in concert. Oxidation of cytoplasmic NADH by the cytosolic form of the enzyme creates glycerol-3-phosphate from dihydroxyacetone phosphate. Once the glycerol-3-phosphate has moved through the inner mitochondrial membrane it can then be oxidised by a separate isoform of glycerol-3-phosphate dehydrogenase that uses quinone as an oxidant and FAD as a co-factor. As a result, there is a net loss in energy, comparable to one molecule of ATP.^[7]

The combined action of these enzymes maintains the NAD+/NADH ratio that allows for continuous operation of metabolism.

Role in disease

The fundamental role of GDPH in maintaining the NAD+/NADH potential, as well as its role in lipid metabolism, makes GDPH a factor in lipid imbalance diseases, such as obesity.

Enhanced GPDH activity, particularly GPD2, leads to an increase in glycerol production. Since glycerol is a main subunit in lipid metabolism, its abundance can easily lead to an increase in triglyceride accumulation at a cellular level. As a result, there is a tendency to form adipose tissue leading to an accumulation of fat that favors obesity.^[12]
GPDH has also been found to play a role in Brugada syndrome. Mutations in the gene encoding GPD1 have been proven to cause defects in the electron transport chain. This conflict with NAD+/NADH levels in the cell is believed to contribute to defects in cardiac sodium ion channel regulation and can lead to a lethal arrythmia during infancy.^[13]

Pharmacological target

The mitochondrial isoform of G3P dehydrogenase is thought to be inhibited by metformin, a first line drug for type 2 diabetes. ^[14]

Structure

Glycerol-3-phosphate dehydrogenase consists of two protein domains. The N-terminal domain is an NAD-binding domain, and the C-terminus acts as a substrate-binding domain.^[15] However, dimer and tetramer interface residues are involved in GAPDH-RNA binding, as GAPDH can exhibit several moonlighting activities, including the modulation of RNA binding and/or stability.^[16]

References

1 2 PDB: 1X0V; Ou X, Ji C, Han X, Zhao X, Li X, Mao Y, Wong LL, Bartlam M, Rao Z (Mar 2006). "Crystal structures of human glycerol 3-phosphate dehydrogenase 1 (GPD1)". Journal of Molecular Biology. 357 (3): 858–69. doi:10.1016/j.jmb.2005.12.074. PMID 16460752.
↑ Ou X, Ji C, Han X, Zhao X, Li X, Mao Y, Wong LL, Bartlam M, Rao Z (Mar 2006). "Crystal structures of human glycerol 3-phosphate dehydrogenase 1 (GPD1)". Journal of Molecular Biology. 357 (3): 858–69. doi:10.1016/j.jmb.2005.12.074. PMID 16460752.
1 2 Harding JW, Pyeritz EA, Copeland ES, White HB (Jan 1975). "Role of glycerol 3-phosphate dehydrogenase in glyceride metabolism. Effect of diet on enzyme activities in chicken liver" (PDF). The Biochemical Journal. 146 (1): 223–9. doi:10.1042/bj1460223. PMC 1165291. PMID 167714.
1 2 Geertman JM, van Maris AJ, van Dijken JP, Pronk JT (Nov 2006). "Physiological and genetic engineering of cytosolic redox metabolism in Saccharomyces cerevisiae for improved glycerol production". Metabolic Engineering. 8 (6): 532–42. doi:10.1016/j.ymben.2006.06.004. PMID 16891140.
↑ Ansell R, Granath K, Hohmann S, Thevelein JM, Adler L (May 1997). "The two isoenzymes for yeast NAD+-dependent glycerol 3-phosphate dehydrogenase encoded by GPD1 and GPD2 have distinct roles in osmoadaptation and redox regulation". The EMBO Journal. 16 (9): 2179–87. doi:10.1093/emboj/16.9.2179. PMC 1169820. PMID 9171333.
↑ Kota V, Rai P, Weitzel JM, Middendorff R, Bhande SS, Shivaji S (Sep 2010). "Role of glycerol-3-phosphate dehydrogenase 2 in mouse sperm capacitation". Molecular Reproduction and Development. 77 (9): 773–83. doi:10.1002/mrd.21218. PMID 20602492.
1 2 Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2002). "Chapter 18.5: Glycerol 3-Phosphate Shuttle". Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4684-0.
↑ Guindalini C, Lee KS, Andersen ML, Santos-Silva R, Bittencourt LR, Tufik S (Jan 2010). "The influence of obstructive sleep apnea on the expression of glycerol-3-phosphate dehydrogenase 1 gene". Experimental Biology and Medicine. 235 (1): 52–6. doi:10.1258/ebm.2009.009150. PMID 20404019.
↑ Bunoust O, Devin A, Avéret N, Camougrand N, Rigoulet M (Feb 2005). "Competition of electrons to enter the respiratory chain: a new regulatory mechanism of oxidative metabolism in Saccharomyces cerevisiae". The Journal of Biological Chemistry. 280 (5): 3407–13. doi:10.1074/jbc.M407746200. PMID 15557339.
↑ Kota V, Dhople VM, Shivaji S (Apr 2009). "Tyrosine phosphoproteome of hamster spermatozoa: role of glycerol-3-phosphate dehydrogenase 2 in sperm capacitation". Proteomics. 9 (7): 1809–26. doi:10.1002/pmic.200800519. PMID 19333995.
↑ Kumar S, Kalyanasundaram GT, Gummadi SN (Feb 2011). "Differential response of the catalase, superoxide dismutase and glycerol-3-phosphate dehydrogenase to different environmental stresses in Debaryomyces nepalensis NCYC 3413". Current Microbiology. 62 (2): 382–7. doi:10.1007/s00284-010-9717-z. PMID 20644932.
↑ Xu SP, Mao XY, Ren FZ, Che HL (Feb 2011). "Attenuating effect of casein glycomacropeptide on proliferation, differentiation, and lipid accumulation of in vitro Sprague-Dawley rat preadipocytes". Journal of Dairy Science. 94 (2): 676–83. doi:10.3168/jds.2010-3827. PMID 21257036.
↑ Van Norstrand DW, Valdivia CR, Tester DJ, Ueda K, London B, Makielski JC, Ackerman MJ (Nov 2007). "Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome". Circulation. 116 (20): 2253–9. doi:10.1161/CIRCULATIONAHA.107.704627. PMC 3332545. PMID 17967976.
↑ Ferrannini E (Oct 2014). "The target of metformin in type 2 diabetes". The New England Journal of Medicine. 371 (16): 1547–8. doi:10.1056/NEJMcibr1409796. PMID 25317875.
↑ Suresh S, Turley S, Opperdoes FR, Michels PA, Hol WG (May 2000). "A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana". Structure. 8 (5): 541–52. doi:10.1016/s0969-2126(00)00135-0. PMID 10801498.
↑ White MR, Khan MM, Deredge D, Ross CR, Quintyn R, Zucconi BE, Wysocki VH, Wintrode PL, Wilson GM, Garcin ED (Jan 2015). "A dimer interface mutation in glyceraldehyde-3-phosphate dehydrogenase regulates its binding to AU-rich RNA". The Journal of Biological Chemistry. 290 (3): 1770–85. doi:10.1074/jbc.M114.618165. PMC 4340419. PMID 25451934.

External links

equivalent entries:
- alphaGPDH at the US National Library of Medicine Medical Subject Headings (MeSH)
- GPDH
Yeast genome database GO term: GPDH
enzyme no. -2053504966 at GPnotebook

This article incorporates text from the public domain Pfam and InterPro IPR011128

This article incorporates text from the public domain Pfam and InterPro IPR006109

Oxidoreductases: alcohol oxidoreductases (EC 1.1)

1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3 Beta 3-beta-HSD NSDHL 11 Beta HSD11B1 HSD11B2 17 Beta

1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)

1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase

1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)

1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase

1.1.99: other acceptors	Choline dehydrogenase L2HGDH

Enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list)

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