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Glycerol-3-phosphate dehydrogenase

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Title: Glycerol-3-phosphate dehydrogenase  
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Subject: Oxidative phosphorylation, Brugada syndrome, Glycerol, Dihydroxyacetone phosphate, Glycerol 3-phosphate, GPD1L
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Glycerol-3-phosphate dehydrogenase

Glycerol-3-phosphate dehydrogenase (NAD+)
EC number CAS number IntEnz BRENDA ExPASy KEGG MetaCyc metabolic pathway
PRIAM PDB structures PDBsum
Gene Ontology EGO
Glycerol-3-phosphate dehydrogenase (quinone)
Identifiers
EC number CAS number IntEnz BRENDA ExPASy KEGG MetaCyc metabolic pathway
PRIAM PDB structures PDBsum
NAD-dependent glycerol-3-phosphate dehydrogenase N-terminus
crystal structure of the n-(1-d-carboxylethyl)-l-norvaline dehydrogenase from arthrobacter sp. strain 1c
Identifiers
Symbol NAD_Gly3P_dh_N
Pfam Pfam clan InterPro PROSITE PDOC00740
SCOP SUPERFAMILY 1m66
NAD-dependent glycerol-3-phosphate dehydrogenase C-terminus
structure of glycerol-3-phosphate dehydrogenase from archaeoglobus fulgidus
Identifiers
Symbol NAD_Gly3P_dh_C
Pfam Pfam clan InterPro PROSITE PDOC00740
SCOP SUPERFAMILY 1m66

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is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate.[2]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

glycerol-3-phosphate dehydrogenase 1 (soluble)
Identifiers
Symbol GPD1
Entrez HUGO OMIM RefSeq UniProt EC number Locus q12-q13
glycerol-3-phosphate dehydrogenase 2 (mitochondrial)
Identifiers
Symbol GPD2
Entrez HUGO OMIM RefSeq UniProt EC number Locus 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]


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.

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

References

Further reading

External links

  • equivalent entries:
    • Medical Subject Headings (MeSH)
    • GPDH
  • Yeast genome database GO term: GPDH
  • enzyme no. GPnotebook


This article incorporates text from the IPR011128

This article incorporates text from the IPR006109

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