| Glycerol-3-phosphate dehydrogenase (NAD+) |
Crystallographic structure of human glycerol-3-phosphate dehydrogenase 1.[1]
|
| Identifiers |
| EC number |
1.1.1.8 |
| CAS number |
9075-65-4 |
| Databases |
| IntEnz |
IntEnz view |
| BRENDA |
BRENDA entry |
| ExPASy |
NiceZyme view |
| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
| Gene Ontology |
AmiGO / EGO |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
|
| Glycerol-3-phosphate dehydrogenase (quinone) |
| Identifiers |
| EC number |
1.1.5.3 |
| CAS number |
9001-49-4 |
| Databases |
| IntEnz |
IntEnz view |
| BRENDA |
BRENDA entry |
| ExPASy |
NiceZyme view |
| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
|
| NAD-dependent glycerol-3-phosphate dehydrogenase N-terminus |
crystal structure of the n-(1-d-carboxylethyl)-l-norvaline dehydrogenase from arthrobacter sp. strain 1c
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| Identifiers |
| Symbol |
NAD_Gly3P_dh_N |
| Pfam |
PF01210 |
| Pfam clan |
CL0063 |
| InterPro |
IPR011128 |
| PROSITE |
PDOC00740 |
| SCOP |
1m66 |
| SUPERFAMILY |
1m66 |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe; PDBj |
| PDBsum |
structure summary |
|
| NAD-dependent glycerol-3-phosphate dehydrogenase C-terminus |
structure of glycerol-3-phosphate dehydrogenase from archaeoglobus fulgidus
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| Identifiers |
| Symbol |
NAD_Gly3P_dh_C |
| Pfam |
PF07479 |
| Pfam clan |
CL0106 |
| InterPro |
IPR006109 |
| PROSITE |
PDOC00740 |
| SCOP |
1m66 |
| SUPERFAMILY |
1m66 |
| Available protein structures: |
| Pfam |
structures |
| PDB |
RCSB PDB; PDBe; PDBj |
| PDBsum |
structure summary |
|
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is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate.[2]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.
Contents
- 1 Metabolic Function
- 2 Reaction
- 3 Variants
- 3.1 GPD1
- 3.2 GPD2
- 3.3 Response to Environmental Stresses
- 4 Glycerol-3-phosphate shuttle
- 5 Role in Disease
- 6 Structure
- 7 See also
- 8 References
- 9 Further reading
- 10 External links
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 that 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.
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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 |
| Locus |
Chr. 12 q12-q13 |
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| glycerol-3-phosphate dehydrogenase 2 (mitochondrial) |
| Identifiers |
| Symbol |
GPD2 |
| Entrez |
2820 |
| HUGO |
4456 |
| OMIM |
138430 |
| RefSeq |
NM_000408 |
| UniProt |
P43304 |
| Other data |
| 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:
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]
X-ray structure of glycerol-3-phosphate dehydrogenase from Bacilius halodurans complexed with FAD. Northeast Structural Genomics Consortium target BhR167.
[11]
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.[12]
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.[13]
- 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.[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]
See also
- substrate pages: glycerol 3-phosphate, dihydroxyacetone phosphate
- related topics: glycerol phosphate shuttle, creatine kinase, glycolysis, gluconeogenesis
References
- ^ a b PDB 1X0V; Ou X, Ji C, Han X, Zhao X, Li X, Mao Y, Wong LL, Bartlam M, Rao Z (March 2006). "Crystal structures of human glycerol 3-phosphate dehydrogenase 1 (GPD1)". J. Mol. Biol. 357 (3): 858–69. doi:10.1016/j.jmb.2005.12.074. PMID 16460752.
- ^ Ou, Xianjin; Ji Chaoneng, Han Xueqing, Zhao Xiaodong, Li Xuemei, Mao Yumin, Wong Luet-Lok, Bartlam Mark, Rao Zihe (31 March 2006). "Crystal Structures of Human Glycerol 3-phosphate Dehydrogenase 1 (GPD1)". Journal of Molecular Biology 357 (3): 858–869. doi:10.1016/j.jmb.2005.12.074. PMID 16460752. Retrieved 14 May 2011.
- ^ a b Harding Jr., Joseph W.; Pyeritz, Eric A.; Copeland, Eric S.; White III, Harold B. (1975). "Role of Glycerol 3-Phosphate Dehydrogenase in Glyceride Metabolism - Effect of Diet on Enzyme Activities in Chicken Liver". Biochem Journal 146: 223–229.
- ^ a b Geertman, Jan-Maarten A.; van Maris, Antonius J.A.; van Dijken, Johannes P.; Rronk, Jack T. (November 2006). "Physiological and genetic engineering of cytosolic redox metabolism in Saccharomyces cerevisiae for improved glycerol production". Metabolic Engineering 8 (6): 532–542. doi:10.1016/j.ymben.2006.06.004. PMID 16891140. Retrieved 14 May 2011.
- ^ Ansell, Ricky; Granath, Katarina ; Hohmann, Stefan ; Thevelein, Johan M. and Adler, Lennart (14 January 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): 2179–2187. doi:10.1093/emboj/16.9.2179. PMC 1169820. PMID 9171333. Retrieved 15 May 2011.
- ^ Kota, Venkatesh; Rai, Priyanka; Weitzel, Joachim m.; Middendorff, Ralf; Bhande, Satish S.; Shivaji, Sisinthy (2 July 2010). "Role of glycerol-3-phosphate dehydrogenase 2 in mouse sperm capacitation". Molecular Reproduction and Development 77 (9): 773–783. doi:10.1002/mrd.21218/full. PMID 20602492.
- ^ a b 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, Camila; Lee, Kil S.; Andersen, Monica L.; Santos-Silva, Rogerio; Bittencourt, Lia Rita A. and Tufik, Sergio (2010). "The influence of obstructive sleep apnea on the expression of glycerol-3-phosphate dehydrogenase1 gene". Experimental Biology and Medicine 235 (1): 52–56. doi:10.1258/ebm.2009.009150. PMID 20404019.
- ^ Bunoust, Odile; Devin, Anne; Averet, Nicole; Camougrand, Nadine and Rigoulet, Michel (4 February 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): 3407–3413. doi:10.1074/jbc.M407746200. PMID 15557339. Retrieved 16 May 2011.
- ^ Kota, Venkatesh; Dhople, Vishnu M. and Shivaji, Sisinthy (2009). "Tyrosine phosphoproteome of hamster spermatozoa: Role of glycerol-3-phosphate dehydrogenase 2 in sperm capacitation". Proteomics 9 (7): 1809–1826. doi:10.1002/pmic.200800519.
- ^ Kuzin, A.P. "X-Ray structure of the glycerol-3-phosphate dehydrogenase from Bacillus halodurans complexed with FAD. Northeast Structural Genomics Consortium target BhR167.". www.pdb.org. Retrieved 16 May 2011.
- ^ Kumar, Sawan; Kalyanasundaram, Gayathiri T. and Gummadi, Sathyanarayana N. (20 July 2010). "Differential Response of the Catalase, Superoxide Dismutase and Glycerol-3-phosphate Dehydrogenase to Different Environmental Stresses in Debaryomyces nepalensis NCYC 3413". Journal of industrial microbiology & biotechnology.
- ^ Xu, S.P; Mao, X.Y.; Ren, F.Z. and Che, H.L. (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): 676–683. doi:10.3168/jds.2010-3827. PMID 21257036.
- ^ Van Norstrand, David W.; Validivia, Carmen R.; Tester, David J; Ueda, Kazuo; London, Barry; Makielski, Jonthan C and Ackerman, michael J. (14 May 2011). "Molecular and Functional Characterization of Novel Glycerol-3-Phosphate Dehydroogenase 1 like Gene (GPD1-L) Mutations in Sudden Infant Death Syndrome". Journal of the American Heart Association 116 (20): 2253–9. doi:10.1161/CIRCULATIONAHA.107.704627. PMID 17967976. Retrieved 18 May 2011.
- ^ 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. PMID 10801498.
Further reading
- Baranowski T (1963). "α-Glycerophosphate dehydrogenase". In Boyer PD, Lardy H, Myrbäck K. The Enzymes (2nd ed.). New York: Academic Press. pp. 85–96.
- Brosemer RW, Kuhn RW (May 1969). "Comparative structural properties of honeybee and rabbit α-glycerophosphate dehydrogenases". Biochemistry 8 (5): 2095–105. doi:10.1021/bi00833a047. PMID 4307630.
- O'Brien SJ, MacIntyre RJ (October 1972). "The -glycerophosphate cycle in Drosophila melanogaster. I. Biochemical and developmental aspects". Biochem. Genet. 7 (2): 141–61. doi:10.1007/BF00486085. PMID 4340553.
- Warkentin DL, Fondy TP (July 1973). "Isolation and characterization of cytoplasmic L-glycerol-3-phosphate dehydrogenase from rabbit-renal-adipose tissue and its comparison with the skeletal-muscle enzyme". Eur. J. Biochem. 36 (1): 97–109. doi:10.1111/j.1432-1033.1973.tb02889.x. PMID 4200180.
- Albertyn J, van Tonder A, Prior BA (August 1992). "Purification and characterization of glycerol-3-phosphate dehydrogenase of Saccharomyces cerevisiae". FEBS Lett. 308 (2): 130–2. doi:10.1016/0014-5793(92)81259-O. PMID 1499720.
- Koekemoer TC, Litthauer D, Oelofsen W (June 1995). "Isolation and characterization of adipose tissue glycerol-3-phosphate dehydrogenase". Int. J. Biochem. Cell Biol. 27 (6): 625–32. doi:10.1016/1357-2725(95)00012-E. PMID 7671141.
- Pahlman, Inga-lill; Larsson, Christer; Averet, Nicole; Bunoust, Odile; Boubekeur, Samira; Gustafsson, Lena and Rigoulet, Michel (2 August 2002). "Kinetic Regulation of the Mitochondrial Glycerol-3-phosphate Dehydrogenase by the External NADH Dehydrogenase in Saccharomyces cerevisiae". The Journal of Biological Chemistry 277 (31): 27991–27995. doi:10.1074/jbc.M204079200. PMID 12032156.
- Overkamp, Karin M.; Bakker, Barbara M.; Kotter, Peter; van Tuijl, Arjen; de Vries, Simon; van Dijken, Johannes P. and Pronk, Jack T. (May 2000). "In Vivo Analysis of the Mechanisms for Oxidation of Cytosolic NADH by Saccharomyces cerevisiae Mitochondria". Journal of Bacteriology 182 (10): 2823–2830. doi:10.1128/JB.182.10.2823-2830.2000. PMC 101991. PMID 10781551. Retrieved 16 May 2011.
- Dawson, Anthony G.; Cooney, Gregory J. (July 1978). "RECONSTRUCTION OF THE wGLYCEROLPHOSPHATE SHUTTLE USING RAT KIDNEY MITOCHONDRIA". Febs Letters 91 (2): 169–172. doi:10.1016/0014-5793(78)81164-8. PMID 210038.
- Opperdoes, Fred R.; Borst, Piet; Bakker, Suzanne and Leene, Wolter (18 October 1976). "Localization of Glycerol-3-Phosphate Oxidase in the Mitochondrion and Particulate NAD+-Linked Glycerol-3-Phosphate Dehydrogenase in the Microbodies of the Bloodstream Form of Trypanosoma brucei". European Journal of Biochemistry 76 (1): 29–39. doi:10.1111/j.1432-1033.1977.tb11567.x. PMID 142010.
- Eswaramoorthy, Subramaniam; Bonanno, Jeffrey B.; Burley, Stephen K. and Swaminathan, Subramanyam (15 June 2006). "Mechanism of action of a flavin-containing monooxygenase". Proceedings of the National Academy of Sciences of the United States of America 103 (26): 9832–9837. doi:10.1073/pnas.0602398103. PMC 1502539. PMID 16777962. Retrieved 16 May 2011.
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
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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
- 11 Beta
- 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
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| 1.1.99: other acceptors |
- Choline dehydrogenase
- L2HGDH
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|
- B
- enzm
- 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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This article incorporates text from the public domain Pfam and InterPro IPR011128
This article incorporates text from the public domain Pfam and InterPro IPR006109