Glycerol-3-phosphate dehydrogenase
Encyclopedia
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that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate
.
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
.
. Through the reduction of dihydroxyacetone phosphate into glycerol 3-phosphate
, GPDH allows the prompt dephosphorylation
of glycerol 3-phosphate
into glycerol
.
Additionally, GPDH is responsible for maintaining the redox potential across the inner mitochondrial membrane
in glycolysis
.
reactions, carrying electrons from one reaction to another. 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
.
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:
The following human genes encode proteins with GPDH enzymatic activity:
As a result, NAD+ is regenerated for further metabolic activity.
GPD1 consists of two subunits, 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).]]
to the electron transport chain
. GPD2 consists of 4 identical subunits.
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.
The combined action of these enzymes maintains the NAD+/NADH ratio that allows for continuous operation of metabolism.
, makes GDPH a factor in lipid imbalance diseases, such as obesity
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate
Glycerol 3-phosphate
Glycerol 3-phosphate is an organophosphate derived from the reaction catalysed by glycerol kinase where ATP + glycerol ADP + sn-glycerol 3-phosphate. It is a component of glycerophospholipids. It should not be confused with the similarly named glycerate 3-phosphate or glyceraldehyde 3-phosphate...
.
Glycerol-3-phosphate dehydrogenase serves as a major link between carbohydrate metabolism
Carbohydrate metabolism
Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....
and lipid metabolism
Lipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
. It is also a major contributor of electrons to the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
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
Glyceraldehyde 3-phosphate dehydrogenase
Glyceraldehyde 3-phosphate dehydrogenase is an enzyme of ~37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules...
(GAPDH) whose substrate is an aldehyde
Aldehyde
An aldehyde is an organic compound containing a formyl group. This functional group, with the structure R-CHO, consists of a carbonyl center bonded to hydrogen and an R group....
not an alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
.
Metabolic Function
GPDH plays a major role in lipid biosynthesisBiosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
. Through the reduction of dihydroxyacetone phosphate into glycerol 3-phosphate
Glycerol 3-phosphate
Glycerol 3-phosphate is an organophosphate derived from the reaction catalysed by glycerol kinase where ATP + glycerol ADP + sn-glycerol 3-phosphate. It is a component of glycerophospholipids. It should not be confused with the similarly named glycerate 3-phosphate or glyceraldehyde 3-phosphate...
, GPDH allows the prompt dephosphorylation
Dephosphorylation
Dephosphorylation is the essential process of removing phosphate groups from an organic compound by hydrolysis. Its opposite is phosphorylation...
of glycerol 3-phosphate
Glycerol 3-phosphate
Glycerol 3-phosphate is an organophosphate derived from the reaction catalysed by glycerol kinase where ATP + glycerol ADP + sn-glycerol 3-phosphate. It is a component of glycerophospholipids. It should not be confused with the similarly named glycerate 3-phosphate or glyceraldehyde 3-phosphate...
into glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
.
Additionally, GPDH is responsible for maintaining the redox potential across the inner mitochondrial membrane
Inner mitochondrial membrane
The mitochondrial inner membrane forms internal compartments known as cristae, which allow greater space for the proteins such as cytochromes to function properly and efficiently. The electron transport chain is located on the inner membrane of the mitochondria...
in glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
.
Reaction
The NAD+/NADH coenzyme couple act as an electron reservoir for metabolic redoxRedox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
reactions, carrying electrons from one reaction to another. Most of these metabolism reactions occur in the mitochondria. To regenerate NAD+ for further use, NADH pools in the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
must be reoxidized. Since the mitochondrial inner membrane is impermeable to both NADH and NAD+, these cannot be freely exchanged between the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
and mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
.
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 cytosolCytosolThe cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, and catalizes the reduction of dihydroxyacetone phosphate into glycerol-3-phosphate. - In conjunction, Mitochondrial GPDH, or GPD2 is embedded on the outersurface the inner mitochondrial membraneInner mitochondrial membraneThe mitochondrial inner membrane forms internal compartments known as cristae, which allow greater space for the proteins such as cytochromes to function properly and efficiently. The electron transport chain is located on the inner membrane of the mitochondria...
, overlooking the cytosolCytosolThe cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
, and catalizes the oxidation of glycerol-3-phosphate to dihydroxyacetone phosphate.
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 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, 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).]]
GPD2
Mitochondrial glycerol-3-phosphate dehydrogenase (GPD2), catalyzes the irreversible oxidation of glycerol-3-phosphate to dihydroxyacetone phosphate and concomitantly transfers two electrons from FADFAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
to the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. GPD2 consists of 4 identical subunits.
Response to Environmental Stresses
- Studies indicate that GPDH is mostly unaffected by pHPHIn chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
changes: neither GPD1 or GPD2 is favored under certain pHPHIn chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...
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 glycerolGlycerolGlycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
in response. - Changes in temperature do not appear to favor neither GPD1 nor GPD2.
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 membraneInner mitochondrial membrane
The mitochondrial inner membrane forms internal compartments known as cristae, which allow greater space for the proteins such as cytochromes to function properly and efficiently. The electron transport chain is located on the inner membrane of the mitochondria...
it can then be oxidised by a separate isoform of glycerol-3-phosphate dehydrogenase that uses quinone
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
as an oxidant and FAD
FAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
as a co-factor. As a result there is a net loss in energy, comparable to one molecule of ATP.
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 metabolismLipid metabolism
Lipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
, makes GDPH a factor in lipid imbalance diseases, such as obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
- Enhanced GPDH activity, particularly GPD2, leads to an increase in glycerolGlycerolGlycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
production. Since glycerolGlycerolGlycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
is a main subunitSubunitA subunit is a subdivision of a larger unit.*In military organizations, a sub-unit is smaller in size than a battalion and is commanded by an Officer Commanding.*In chemistry, the term can refer to a monomer...
in lipid metabolismLipid metabolismLipid metabolism refers to the processes that involve the intercourse and degradation of lipids.The types of lipids involved include:* Bile salts* Cholesterols* Eicosanoids* Glycolipids* Ketone bodies* Fatty acids - see also fatty acid metabolism...
, its abundance can easily lead to an increase in triglycerideTriglycerideA triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
accumulation at a cellular level. As a result, there is a tendency to form adipose tissueAdipose tissueIn histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
leading to an accumulation of fatFatFats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...
that favors obesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
- GPDH has also been found to play a role in Brugada syndromeBrugada syndromeThe Brugada syndrome is a genetic disease that is characterised by abnormal electrocardiogram findings and an increased risk of sudden cardiac death. It is named by the Spanish cardiologists Pedro Brugada and Josep Brugada...
. Mutations in the geneGeneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
encoding GPD1 have been proven to cause defects in the electron transport chainElectron transport chainAn electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. This conflict with NAD+/NADH levels in the cell is believed to contribute to defects in cardiac sodium ion channelSodium ion channelSodium channels are integral membrane proteins that form ion channels, conducting sodium ions through a cell's plasma membrane. They are classified according to the trigger that opens the channel for such ions, i.e...
regulation and can lead to a lethal arrythmia during infancy.
See also
- substrate pages: glycerol 3-phosphateGlycerol 3-phosphateGlycerol 3-phosphate is an organophosphate derived from the reaction catalysed by glycerol kinase where ATP + glycerol ADP + sn-glycerol 3-phosphate. It is a component of glycerophospholipids. It should not be confused with the similarly named glycerate 3-phosphate or glyceraldehyde 3-phosphate...
, dihydroxyacetone phosphate - related topics: glycerol phosphate shuttleGlycerol phosphate shuttleThe glycerol-3-phosphate shuttle is a mechanism that regenerates NAD+ from NADH, a by-product of glycolysis. Its importance in transporting reducing equivalents is secondary to the malate-aspartate shuttle.-Reaction:...
, creatine kinaseCreatine kinaseCreatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
, glycolysisGlycolysisGlycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
, gluconeogenesisGluconeogenesisGluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....