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 one of the enzymes involved in maintaining the redox potential across the inner mitochondrial membrane.^[3]

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 localized to the outer membrane of the mitochondria facing the 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:

There are two forms of GPDH:

The following human genes encode proteins with GPDH enzymatic activity:

GPD1 edit

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 edit

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 edit

• 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.

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]

The mitochondrial isoform of G3P dehydrogenase is thought to be inhibited by metformin, a first line drug for type 2 diabetes. ^[14]

Biological Research edit

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.

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]

• substrate pages: glycerol 3-phosphate, dihydroxyacetone phosphate
• related topics: glycerol phosphate shuttle, creatine kinase, glycolysis, gluconeogenesis

• equivalent entries:
  • alphaGPDH at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • GPDH
• Yeast genome database GO term: GPDH Archived 2007-12-24 at the Wayback Machine