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22  structures 4754  species 2  interactions 5512  sequences 20  architectures

Family: NAD_Gly3P_dh_C (PF07479)

Summary: NAD-dependent glycerol-3-phosphate dehydrogenase C-terminus

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This is the Wikipedia entry entitled "Glycerol-3-phosphate dehydrogenase". More...

Glycerol-3-phosphate dehydrogenase Edit Wikipedia article

Glycerol-3-phosphate dehydrogenase (NAD+)
Glycerol-3-phosphate dehydrogenase 1.png
Crystallographic structure of human glycerol-3-phosphate dehydrogenase 1.[1]
Identifiers
EC number 1.1.1.8
CAS number 9075-65-4
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
Glycerol-3-phosphate dehydrogenase (quinone)
Identifiers
EC number 1.1.5.3
CAS number 9001-49-4
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
NAD-dependent glycerol-3-phosphate dehydrogenase N-terminus
PDB 1bg6 EBI.jpg
crystal structure of the n-(1-d-carboxylethyl)-l-norvaline dehydrogenase from arthrobacter sp. strain 1c
Identifiers
Symbol NAD_Gly3P_dh_N
Pfam PF01210
Pfam clan CL0063
InterPro IPR011128
PROSITE PDOC00740
SCOP 1m66
SUPERFAMILY 1m66
NAD-dependent glycerol-3-phosphate dehydrogenase C-terminus
PDB 1txg EBI.jpg
structure of glycerol-3-phosphate dehydrogenase from archaeoglobus fulgidus
Identifiers
Symbol NAD_Gly3P_dh_C
Pfam PF07479
Pfam clan CL0106
InterPro IPR006109
PROSITE PDOC00740
SCOP 1m66
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is an enzyme that catalyzes the reversible redox conversion of dihydroxyacetone phosphate (aka glycerone phosphate, outdated) to sn-glycerol 3-phosphate.[2]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[edit]

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]

Fig. 1. Schematic overview of fermentative and oxidative glucose metabolism of Saccharomyces cerevisiae. (A) upper part of glycolysis, which includes two sugar phosphorylation reactions. (B) fructose-1,6-bisphosphate aldolase, splitting the C6-molecule into two triose phosphates (C) triosephosphate isomerase, interconverting DHAP and GAP. (D) glycerol pathway reducing DHAP to glycerol-3-phosphate (G3P) by G3P dehydrogenase, followed by dephosphorylation to glycerol by G3Pase. (E) The lower part of glycolysis converts GAP to pyruvate while generating 1 NADH and 2 ATP via a series of 5 enzymes. (F) Alcoholic fermentation; decarboxylation of pyruvate by pyruvate decarboxylase, followed by reduction of acetaldehyde to ethanol. (G) mitochondrial pyruvate-dehydrogenase converts pyruvate to acetyl-CoA, which enters the tricarboxylic acid cycle. (H) external mitochondrial NADH dehydrogenases. (I) mitochondrial G3P dehydrogenase. Electrons of these three dehydrogenases enter the respiratory chain that the level of the quinol pool (Q). (J) internal mitochondrial NADH dehydrogenase. (K) ATP synthase. (L) generalized scheme of NADH shuttle. (M) formate oxidation by formate dehydrogenase.[4]

Reaction[edit]

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:

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.

Variants[edit]

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 2819
HUGO 4455
OMIM 138420
RefSeq NM_005276
UniProt P21695
Other data
Locus Chr. 12 q12-q13
glycerol-3-phosphate dehydrogenase 2 (mitochondrial)
Identifiers
Symbol GPD2
Entrez 2820
HUGO 4456
OMIM 138430
RefSeq NM_000408
UniProt P43304
Other data
Locus Chr. 2 q24.1

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:

GPD1 Reaction Mechanism

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]

X-ray structure of glycerol-3-phosphate dehydrogenase from Bacilius halodurans complexed with FAD. Northeast Structural Genomics Consortium target BhR167.[11]
GPD2 Reaction Mechanism

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.[12]

Glycerol-3-phosphate shuttle[edit]

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[edit]

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[edit]

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[edit]

References[edit]

  1. ^ a b PDB 1X0V; Ou X, Ji C, Han X, Zhao X, Li X, Mao Y, Wong LL, Bartlam M, Rao Z (March 2006). "Crystal structures of human glycerol 3-phosphate dehydrogenase 1 (GPD1)". J. Mol. Biol. 357 (3): 858–69. doi:10.1016/j.jmb.2005.12.074. PMID 16460752. 
  2. ^ Ou, Xianjin; Ji Chaoneng, Han Xueqing, Zhao Xiaodong, Li Xuemei, Mao Yumin, Wong Luet-Lok, Bartlam Mark, Rao Zihe (31 March 2006). "Crystal Structures of Human Glycerol 3-phosphate Dehydrogenase 1 (GPD1)". Journal of Molecular Biology 357 (3): 858–869. doi:10.1016/j.jmb.2005.12.074. PMID 16460752. Retrieved 14 May 2011. 
  3. ^ a b Harding Jr., Joseph W.; Pyeritz, Eric A.; Copeland, Eric S.; White III, Harold B. (1975). "Role of Glycerol 3-Phosphate Dehydrogenase in Glyceride Metabolism - Effect of Diet on Enzyme Activities in Chicken Liver". Biochem Journal 146: 223–229. 
  4. ^ a b Geertman, Jan-Maarten A.; van Maris, Antonius J.A.; van Dijken, Johannes P.; Rronk, Jack T. (November 2006). "Physiological and genetic engineering of cytosolic redox metabolism in Saccharomyces cerevisiae for improved glycerol production". Metabolic Engineering 8 (6): 532–542. doi:10.1016/j.ymben.2006.06.004. PMID 16891140. Retrieved 14 May 2011. 
  5. ^ Ansell, Ricky; Granath, Katarina ; Hohmann, Stefan ; Thevelein, Johan M. and Adler, Lennart (14 January 1997). "The two isoenzymes for yeast NAD+-dependent glycerol 3-phosphate dehydrogenase encoded by GPD1 and GPD2 have distinct roles in osmoadaptation and redox regulation". The EMBO Journal 16 (9): 2179–2187. doi:10.1093/emboj/16.9.2179. PMC 1169820. PMID 9171333. Retrieved 15 May 2011. 
  6. ^ Kota, Venkatesh; Rai, Priyanka; Weitzel, Joachim m.; Middendorff, Ralf; Bhande, Satish S.; Shivaji, Sisinthy (2 July 2010). "Role of glycerol-3-phosphate dehydrogenase 2 in mouse sperm capacitation". Molecular Reproduction and Development 77 (9): 773–783. doi:10.1002/mrd.21218/full. PMID 20602492. 
  7. ^ a b Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2002). "Chapter 18.5: Glycerol 3-Phosphate Shuttle". Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-4684-0. 
  8. ^ Guindalini, Camila; Lee, Kil S.; Andersen, Monica L.; Santos-Silva, Rogerio; Bittencourt, Lia Rita A. and Tufik, Sergio (2010). "The influence of obstructive sleep apnea on the expression of glycerol-3-phosphate dehydrogenase1 gene". Experimental Biology and Medicine 235 (1): 52–56. doi:10.1258/ebm.2009.009150. PMID 20404019. 
  9. ^ Bunoust, Odile; Devin, Anne; Averet, Nicole; Camougrand, Nadine and Rigoulet, Michel (4 February 2005). "Competition of Electrons to Enter the Respiratory Chain: A New Regulatory Mechanism of Oxidative Metabolism in Saccharomyces Cerevisiae". The Journal of Biological Chemistry 280 (5): 3407–3413. doi:10.1074/jbc.M407746200. PMID 15557339. Retrieved 16 May 2011. 
  10. ^ Kota, Venkatesh; Dhople, Vishnu M. and Shivaji, Sisinthy (2009). "Tyrosine phosphoproteome of hamster spermatozoa: Role of glycerol-3-phosphate dehydrogenase 2 in sperm capacitation". Proteomics 9 (7): 1809–1826. doi:10.1002/pmic.200800519. PMID 200800519. 
  11. ^ Kuzin, A.P. "X-Ray structure of the glycerol-3-phosphate dehydrogenase from Bacillus halodurans complexed with FAD. Northeast Structural Genomics Consortium target BhR167.". www.pdb.org. Retrieved 16 May 2011. 
  12. ^ Kumar, Sawan; Kalyanasundaram, Gayathiri T. and Gummadi, Sathyanarayana N. (20 July 2010). "Differential Response of the Catalase, Superoxide Dismutase and Glycerol-3-phosphate Dehydrogenase to Different Environmental Stresses in Debaryomyces nepalensis NCYC 3413". Journal of industrial microbiology & biotechnology. 
  13. ^ Xu, S.P; Mao, X.Y.; Ren, F.Z. and Che, H.L. (2011). "attenuating effect of casein glycomacropeptide on proliferation, differentiation, and lipid accumulation of in vitro Sprague-Dawley rat preadipocytes". Journal of Dairy Science 94 (2): 676–683. doi:10.3168/jds.2010-3827. PMID 21257036. 
  14. ^ Van Norstrand, David W.; Validivia, Carmen R.; Tester, David J; Ueda, Kazuo; London, Barry; Makielski, Jonthan C and Ackerman, michael J. (14 May 2011). "Molecular and Functional Characterization of Novel Glycerol-3-Phosphate Dehydroogenase 1 like Gene (GPD1-L) Mutations in Sudden Infant Death Syndrome". Journal of the American Heart Association 116 (20): 2253–9. doi:10.1161/CIRCULATIONAHA.107.704627. PMID 17967976. Retrieved 18 May 2011. 
  15. ^ Suresh S, Turley S, Opperdoes FR, Michels PA, Hol WG (May 2000). "A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana". Structure 8 (5): 541–52. PMID 10801498. 

Further reading[edit]

  • Baranowski T (1963). "α-Glycerophosphate dehydrogenase". In Boyer PD, Lardy H, Myrbäck K. The Enzymes (2nd ed.). New York: Academic Press. pp. 85–96. 
  • Brosemer RW, Kuhn RW (May 1969). "Comparative structural properties of honeybee and rabbit α-glycerophosphate dehydrogenases". Biochemistry 8 (5): 2095–105. doi:10.1021/bi00833a047. PMID 4307630. 
  • O'Brien SJ, MacIntyre RJ (October 1972). "The -glycerophosphate cycle in Drosophila melanogaster. I. Biochemical and developmental aspects". Biochem. Genet. 7 (2): 141–61. doi:10.1007/BF00486085. PMID 4340553. 
  • Warkentin DL, Fondy TP (July 1973). "Isolation and characterization of cytoplasmic L-glycerol-3-phosphate dehydrogenase from rabbit-renal-adipose tissue and its comparison with the skeletal-muscle enzyme". Eur. J. Biochem. 36 (1): 97–109. doi:10.1111/j.1432-1033.1973.tb02889.x. PMID 4200180. 
  • Albertyn J, van Tonder A, Prior BA (August 1992). "Purification and characterization of glycerol-3-phosphate dehydrogenase of Saccharomyces cerevisiae". FEBS Lett. 308 (2): 130–2. doi:10.1016/0014-5793(92)81259-O. PMID 1499720. 
  • Koekemoer TC, Litthauer D, Oelofsen W (June 1995). "Isolation and characterization of adipose tissue glycerol-3-phosphate dehydrogenase". Int. J. Biochem. Cell Biol. 27 (6): 625–32. doi:10.1016/1357-2725(95)00012-E. PMID 7671141. 

External links[edit]

This article incorporates text from the public domain Pfam and InterPro IPR011128

This article incorporates text from the public domain Pfam and InterPro IPR006109

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

NAD-dependent glycerol-3-phosphate dehydrogenase C-terminus Provide feedback

NAD-dependent glycerol-3-phosphate dehydrogenase (GPDH) catalyses the interconversion of dihydroxyacetone phosphate and L-glycerol-3-phosphate. This family represents the C-terminal substrate-binding domain [2].

Literature references

  1. Pahlman IL, Larsson C, Averet N, Bunoust O, Boubekeur S, Gustafsson L, Rigoulet M; , J Biol Chem 2002;277:27991-27995.: Kinetic regulation of the mitochondrial glycerol-3-phosphate dehydrogenase by the external NADH dehydrogenase in Saccharomyces cerevisiae. PUBMED:12032156 EPMC:12032156

  2. Suresh S, Turley S, Opperdoes FR, Michels PA, Hol WG; , Structure Fold Des 2000;8:541-552.: A potential target enzyme for trypanocidal drugs revealed by the crystal structure of NAD-dependent glycerol-3-phosphate dehydrogenase from Leishmania mexicana. PUBMED:10801498 EPMC:10801498


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006109

NAD-dependent glycerol-3-phosphate dehydrogenase (EC) (GPD) catalyzes the reversible reduction of dihydroxyacetone phosphate to glycerol-3-phosphate. It is a cytoplasmic protein, active as a homodimer [PUBMED:2500660], each monomer containing an N-terminal NAD binding site [PUBMED:6773774]. In insects, it acts in conjunction with a mitochondrial alpha-glycerophosphate oxidase in the alpha-glycerophosphate cycle, which is essential for the production of energy used in insect flight [PUBMED:2500660].

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan 6PGD_C (CL0106), which contains the following 6 members:

3HCDH 6PGD IlvC Mannitol_dh_C NAD_Gly3P_dh_C UDPG_MGDP_dh

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(2018)
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(881)
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(1177)
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Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD, Bateman A, Moxon SJ
Number in seed: 27
Number in full: 5512
Average length of the domain: 143.50 aa
Average identity of full alignment: 41 %
Average coverage of the sequence by the domain: 42.43 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 27.2 26.3
Noise cut-off 24.3 24.6
Model length: 149
Family (HMM) version: 9
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Interactions

There are 2 interactions for this family. More...

NAD_Gly3P_dh_C NAD_Gly3P_dh_N

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the NAD_Gly3P_dh_C domain has been found. There are 22 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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