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.
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]
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]
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
outer 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 GPDH in maintaining the
NAD+/
NADH potential, as well as its role in
lipid metabolism, makes GPDH 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]
Biological Research
Sarcophaga barbata was used to study the oxidation of L-3-glycerophosphate in mitochondria. It is found that the L-3-glycerophosphate does not enter the mitochondrial matrix, unlike pyruvate. This helps locate the L-3-glycerophosphate-flavoprotein oxidoreductase, which is on the inner membrane of the mitochondria.
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]
^
abPDB:
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^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.
PMID16460752.
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abGeertman 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.
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10.1016/j.ymben.2006.06.004.
PMID16891140.
^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.
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^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.
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^Ferrannini E (Oct 2014). "The target of metformin in type 2 diabetes". The New England Journal of Medicine. 371 (16): 1547–8.
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Baranowski T (1963). "α-Glycerophosphate dehydrogenase". In Boyer PD, Lardy H, Myrbäck K (eds.). The Enzymes (2nd ed.). New York: Academic Press. pp. 85–96.
Koekemoer TC, Litthauer D, Oelofsen W (Jun 1995). "Isolation and characterization of adipose tissue glycerol-3-phosphate dehydrogenase". The International Journal of Biochemistry & Cell Biology. 27 (6): 625–32.
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