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is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate.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]
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:
The reactions catalyzed by cytosolic (soluble) and mitochondrial GPDH are as follows:
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:
GPD1
Cytosolic Glycerol-3-phosphate dehydrogenase (GPD1), is an NAD+-dependent enzyme[8] that reduces dihydroxyacetone phosphate to glycerol-3-phosphate. Simultaneously, NADH is reduced 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]
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
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.
See also
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). "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. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WK7-4J2KXDT-3&_user=145269&_coverDate=03%2F31%2F2006&_rdoc=1&_fmt=high&_orig=gateway&_origin=gateway&_sort=d&_docanchor=&view=c&_acct=C000012078&_version=1&_urlVersion=0&_userid=145269&md5=a047047ccd322930394768588dba1c26&searchtype=a. 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. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WN3-4K9BSM8-2&_user=145269&_coverDate=11%2F30%2F2006&_rdoc=1&_fmt=high&_orig=gateway&_origin=gateway&_sort=d&_docanchor=&view=c&_acct=C000012078&_version=1&_urlVersion=0&_userid=145269&md5=363ad60a14e74b4b423c442589419cea&searchtype=a#bib2. Retrieved 14 May 2011.
- ^ Ansell, Ricky; Granath, Katarina ; Hohmann, Stefan ; Thevelein, Johan M. and Adler, Lennart (14). "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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1169820. Retrieved 15 May 2011.
- ^ Kota, Venkatesh; Rai, Priyanka; Weitzel, Joachim m.; Middendorff, Ralf; Bhande, Satish S.; Shivaji, Sisinthy (2). "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. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=stryer&part=A2548&rendertype=figure&id=A2548.
- ^ 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. http://ebm.rsmjournals.com/cgi/content/full/235/1/52.
- ^ Bunoust, Odile; Devin, Anne; Averet, Nicole; Camougrand, Nadine and Rigoulet, Michel (4). "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. http://www.jbc.org/content/280/5/3407.full. 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. PMID 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. http://www.pdb.org/pdb/explore/explore.do?structureId=3DA1. Retrieved 16 May 2011.
- ^ Kumar, Sawan; Kalyanasundaram, Gayathiri T. and Gummadi, Sathyanarayana N. (20). "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). "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. http://circ.ahajournals.org/cgi/content/full/116/20/2253. Retrieved 18 May 2011.
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). "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. http://www.jbc.org/content/277/31/27991.full.
- 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=101991. 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). "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). "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. http://www.pnas.org/content/103/26/9832.full. Retrieved 16 May 2011.
External links