Glycerol-3-phosphate dehydrogenase
| Glycerol-3-phosphate dehydrogenase (NAD+) | |||||||||
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| File:Glycerol-3-phosphate dehydrogenase 1.png
Crystallographic structure of human glycerol-3-phosphate dehydrogenase 1.[1]
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| Identifiers | |||||||||
| EC number | 1.1.1.8 | ||||||||
| CAS number | Template:CAS | ||||||||
| 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 | ||||||||
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| Glycerol-3-phosphate dehydrogenase (quinone) | |||||||||
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| Identifiers | |||||||||
| EC number | 1.1.5.3 | ||||||||
| CAS number | Template:CAS | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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| NAD-dependent glycerol-3-phosphate dehydrogenase N-terminus | |||||||||
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| File:PDB 1bg6 EBI.jpg
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 | ||||||||
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| NAD-dependent glycerol-3-phosphate dehydrogenase C-terminus | |||||||||
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| File:PDB 1txg EBI.jpg
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 | ||||||||
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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
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:
- 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:
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File:GPDH shuttle.png
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 | |||||
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| 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:
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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]
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
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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]
See also
- substrate pages: glycerol 3-phosphate, dihydroxyacetone phosphate
- related topics: glycerol phosphate shuttle, creatine kinase, glycolysis, gluconeogenesis
References
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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
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