Glycerol-3-phosphate dehydrogenase (GPDH) is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that catalyzes the reversible redox conversion of

dihydroxyacetone phosphate Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; Co ...

(a.k.a. glycerone phosphate, outdated) to sn-

glycerol 3-phosphate ''sn''-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of two stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of bacterial and eukaryotic glycerophospholi ...

. Glycerol-3-phosphate dehydrogenase serves as a major link between

carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...

and

lipid metabolism Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown and storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. In ani ...

. It is also a major contributor of electrons to the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

in the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

. 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 (abbreviated GAPDH) () is an enzyme of about 37kDa that catalyzes the sixth step of glycolysis and thus serves to break down glucose for energy and carbon molecules. In addition to this long establis ...

(GAPDH), whose substrate is an

aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...

not an

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

Metabolic function

GPDH plays a major role in lipid

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

. Through the reduction of

into

, GPDH allows the prompt

dephosphorylation In biochemistry, dephosphorylation is the removal of a phosphate () group from an organic compound by hydrolysis. It is a reversible post-translational modification. Dephosphorylation and its counterpart, phosphorylation, activate and deactivate e ...

into

glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...

. Additionally, GPDH is one of the enzymes involved in maintaining the

redox potential Redox potential (also known as oxidation / reduction potential, ''ORP'', ''pe'', ''E_'', or E_) is a measure of the tendency of a chemical species to acquire electrons from or lose electrons to an electrode and thereby be reduced or oxidised respe ...

across the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

Schematic overview of fermentative and oxidative glucose metabolism of Saccharomyc

Reaction

The

NAD+ Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

coenzyme A cofactor is a non-protein chemical compound or Metal ions in aqueous solution, metallic ion that is required for an enzyme's role as a catalysis, catalyst (a catalyst is a substance that increases the rate of a chemical reaction). Cofactors can ...

couple act as an electron reservoir for metabolic

redox Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...

reactions, carrying electrons from one reaction to another. Most of these metabolism reactions occur in the

. To regenerate

for further use,

pools in the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

must be reoxidized. Since the

mitochondrial inner membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

is impermeable to both

and

, these cannot be freely exchanged between the

and

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. It can also be referred as the mitochondrial fluid. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitoc ...

. One way to shuttle this reducing equivalent across the membrane is through the

Glycerol-3-phosphate shuttle The glycerol-3-phosphate shuttle is a mechanism used in skeletal muscle and the brain that regenerates NAD+ from NADH, a by-product of glycolysis. NADH is a reducing equivalent that stores electrons generated in the cytoplasm during glycolysis. NA ...

, which employs the two forms of GPDH: *Cytosolic GPDH, or GPD1, is localized to the outer membrane of the mitochondria facing the

, and catalyzes the reduction of

into

glycerol-3-phosphate ''sn''-Glycerol 3-phosphate is the organic ion with the formula HOCH2CH(OH)CH2OPO32-. It is one of two stereoisomers of the ester of dibasic phosphoric acid (HOPO32-) and glycerol. It is a component of bacterial and eukaryotic glycerophospholip ...

. *In conjunction, Mitochondrial GPDH, or GPD2, is embedded on the outer surface of the

, overlooking the

, and catalyzes the oxidation of

. The reactions catalyzed by cytosolic (soluble) and mitochondrial GPDH are as follows:

Variants

There are two forms of GPDH: The following human genes encode proteins with GPDH enzymatic activity:

GPD1

Cytosolic Glycerol-3-phosphate dehydrogenase (GPD1), is an

-dependent enzyme that reduces

. Simultaneously,

is oxidized to

in the following reaction: GPD1 Reaction Mechanism

As a result,

is regenerated for further metabolic activity. GPD1 consists of two subunits, and reacts with

and

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

and concomitantly transfers two electrons from

FAD A fad, trend, or craze is any form of collective behavior that develops within a culture, a generation, or social group in which a group of people enthusiastically follow an impulse for a short time period. Fads are objects or behaviors tha ...

to the

. GPD2 consists of 4 identical subunits. GPD2 Reaction Mechanism

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 Sodium chloride , commonly known as edible salt, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. It is transparent or translucent, brittle, hygroscopic, and occurs as the mineral hali ...

), GPD1 activity is enhanced over GPD2, since an increase in the salinity of the medium leads to an accumulation of

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

by the cytosolic form of the enzyme creates

from dihydroxyacetone phosphate. Once the glycerol-3-phosphate has moved through the

outer mitochondrial membrane A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

it can then be oxidised by a separate isoform of glycerol-3-phosphate dehydrogenase that uses

quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...

as an oxidant and

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

ratio that allows for continuous operation of metabolism.

Role in disease

The fundamental role of GPDH in maintaining the

potential, as well as its role in

, makes GPDH a factor in lipid imbalance diseases, such as

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

. *Enhanced GPDH activity, particularly GPD2, leads to an increase in

production. Since

is a main subunit in

, its abundance can easily lead to an increase in

triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...

accumulation at a cellular level. As a result, there is a tendency to form

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

leading to an accumulation of

fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers specif ...

that favors

. *GPDH has also been found to play a role in Brugada syndrome. Mutations in the

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

encoding GPD1 have been proven to cause defects in the

. This conflict with

levels in the cell is believed to contribute to defects in cardiac

sodium ion channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell (biology), cell's cell membrane, membrane. They belong to the Cation channel superfamily, superfamily of cation channels. Classific ...

regulation and can lead to a lethal

arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...

during infancy.

Pharmacological target

The mitochondrial isoform of G3P dehydrogenase is thought to be inhibited by

metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...

, a first line drug for

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

Biological Research

Sarcophaga barbata ''Sarcophaga barbata'' is a species from the genus '' Sarcophaga'' and the family of flesh fly, ''Sarcophagidae''. It is most closely related to ''S. plinthopyga'', ''S. securifera'', and ''S. bullata'' of the same genus. The species was first ...

'' 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 In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of se ...

. The

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

domain is an

NAD NAD or Nad may refer to: Geography * Nad, County Cork, a village in Ireland * North American Datum, a series of geographic coordinate systems * North Atlantic Drift, an Atlantic Ocean current * Hobli, a subdivision of a taluka in southern Ind ...

-binding domain, and the

C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

acts as a substrate-binding domain. 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.

References

External links

* equivalent entries: ** *
GPDH
* Yeast genome database GO term
GPDH
{{DEFAULTSORT:Glycerol-3-Phosphate Dehydrogenase Protein domains EC 1.1.1

Metabolic function

Reaction

Variants

GPD1

GPD2

Response to environmental stresses

Glycerol-3-phosphate shuttle

Role in disease

Pharmacological target

Biological Research

Structure

See also

References

Further reading

External links