GDP-mannose 4,6-dehydratase

GDP-mannose 4,6-dehydratase
Identifiers
EC no.	4.2.1.47
CAS no.	37211-59-9
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 / QuickGO
Search PMC articles PubMed articles NCBI proteins

The enzyme GDP-mannose 4,6-dehydratase (EC 4.2.1.47) catalyzes the chemical reaction

GDP-mannose ${\displaystyle \rightleftharpoons }$ GDP-4-dehydro-6-deoxy-D-mannose + H₂O

This enzyme belongs to the family of lyases, specifically the hydro-lyases, which cleave carbon-oxygen bonds. The systematic name of this enzyme class is GDP-mannose 4,6-hydro-lyase (GDP-4-dehydro-6-deoxy-D-mannose-forming). Other names in common use include guanosine 5'-diphosphate-D-mannose oxidoreductase, guanosine diphosphomannose oxidoreductase, guanosine diphosphomannose 4,6-dehydratase, GDP-D-mannose dehydratase, GDP-D-mannose 4,6-dehydratase, Gmd, and GDP-mannose 4,6-hydro-lyase. This enzyme participates in fructose and mannose metabolism. It employs one cofactor, NAD⁺.

GDP-Mannose 4, 6-Dehydratase Reaction

The enzyme GDP-Mannose 4, 6-Dehydratase is in the lyase family of enzymes, specifically the hydro-lyases. Other names in use include guanosine 5'-diphosphate-D-mannose oxidoreductase, guanosine diphosphomannose oxidoreductase, guanosine diphosphomannose 4,6-dehydratase, GDP-D-mannose dehydratase, GDP-D-mannose 4,6-dehydratase, GMD, and GDP-mannose 4,6-hydro-lyase. The enzyme is a part of the GDP-Fucose de novo synthesis pathway and catalyzes the first step in the process that gives us GDP-Fucose which is essential for the transfer of Fucose sugars. Its primary structure contains 372 amino acids. This is an essential enzyme in that fucose plays a major role in cell immunity and signaling. Currently GDP-Mannose 4, 6-Dehydratase is not the target of any available drugs, however it is being experimentally targeted with the drug Guanosine-5'-Diphosphate. The chemical reaction of GDP-Mannose 4, 6-Dehydratase is as shown:

GDP-mannose ↔ GDP-4-dehydro-6-deoxy-D-mannose + H₂O

Factors In The Reaction

The enzymes substrate, what the enzyme is acting on, is the GDP-Mannose substance. No other substrates are use this enzyme for reactions.

When the enzyme undergoes its catalyzing process the main product is gets is when it converts GDP-mannose to GDP-4-dehydro-6-deoxy-D-mannose which is then subsequently converted to GDP-Fucose which is crucial for the body to process correctly. It acts as an intermediate step between GDP-Mannose and GDP-Fucose.

In the reaction that the enzyme uses it requires only one cofactor, a compound required for activation, which is NADP(+) however it is uncertain if this compound truly activates the enzyme.

GDP-Fucose is an allosteric inhibitor of the enzyme. ^[1]

Here is a pymol view of the entire structure of the GDP-Mannose 4, 6-Dehydratase enzyme.

GDP-Fucose Biosynthesis Pathway

The enzyme GDP-Mannose 4, 6-Dehydratase is only present in one pathway that we know of. This pathway is the GDP-mannose-dependent de novo pathway which provides most of the bodies GDP-Fucose whereas minor amounts come from fucose salvaging in the body.

Here we can see the full crystal structure of the GDP enzyme. Use this link to find the subunits of the enzyme http://www.rcsb.org/pdb/explore/jmol.do?structureId=1RPN&opt=3 PDB 1rpn

In the pathway the enzyme is in an intermediate step that converts GDP-Mannose to GDP-4-dehydro-6-deoxy-D-mannose which is then converted into GDP-Fucose which is absolutely crucial to the body. The product of this pathway is fucosyltransferases which is then used in a different pathway that creates fucosylated glycans which is used for cell signaling and immunity in the body. Fucose is a deoxyhexose that is present in a wide variety of organisms. In most mammals, fucose-containing glycans have important roles in blood transfusion reactions, selectin-mediated leukocyte-endothelial adhesion, host-microbe interactions, and numerous ontogenic events. Along with those the body uses fucose as signaling branches of a cell and also as identification systems in immunity. However the enzyme only works at its top levels under normal body conditions. Increased pH or heat could severely denature the protein causing the enzyme to malfunction.

GDP-Mannose 4, 6-dehydratase Structure

The enzyme contains four different subunits. Here is a link for a 3-D view of the enzyme http://www.rcsb.org/pdb/explore/jmol.do?structureId=1RPN&bionumber=1

Structural studies

As of late 2007, 5 structures have been solved for this class of enzymes, with PDB accession codes 1DB3, 1N7G, 1N7H, 1RPN, and 1T2A.

References

1. Allen, John G.; Mujacic, Mirna; Frohn, Michael J.; Pickrell, Alex J.; Kodama, Paul; Bagal, Dhanashri; San Miguel, Tisha; Sickmier, E. Allen; Osgood, Steve (2016-10-21). "Facile Modulation of Antibody Fucosylation with Small Molecule Fucostatin Inhibitors and Cocrystal Structure with GDP-Mannose 4,6-Dehydratase". ACS Chemical Biology. 11 (10): 2734–2743. doi:10.1021/acschembio.6b00460. ISSN   1554-8929. OSTI   1330878. PMID   27434622.

• Elbein AD, Heath EC (1965). "The Biosynthesis of Cell Wall Lipopolysaccharide in Escherichia Coli. Ii. Guanosine Diphosphate 4-Keto-6-Deoxy-D-Mannose, an Intermediate in the Biosynthesis of Guanosine Diphosphate Colitose". J. Biol. Chem. 240 (5): 1926–31. doi: 10.1016/S0021-9258(18)97406-5 . PMID   14299611.
• Liao TH, Barber GA (1972). "Purification of guanosine 5'-diphosphate D-mannose oxidoreductase from Phaseolus vulgaris". Biochim. Biophys. Acta. 276 (1): 85–93. doi:10.1016/0005-2744(72)90010-1. PMID   5047712.
• Melo A, Elliott WH, Glaser L (1968). "The mechanism of 6-deoxyhexose synthesis. I. Intramolecular hydrogen transfer catalyzed by deoxythymidine diphosphate D-glucose oxidoreductase". J. Biol. Chem. 243 (7): 1467–74. doi: 10.1016/S0021-9258(18)93566-0 . PMID   4869560.
• Sullivan FX, Kumar R, Kriz R, Stahl M, Xu GY, Rouse J, Chang XJ, Boodhoo A, Potvin B, Cumming DA (1998). "Molecular cloning of human GDP-mannose 4,6-dehydratase and reconstitution of GDP-fucose biosynthesis in vitro". J. Biol. Chem. 273 (14): 8193–202. doi: 10.1074/jbc.273.14.8193 . PMID   9525924.
• Kneidinger B, Graninger M, Adam G, Puchberger M, Kosma P, Zayni S, Messner P (2001). "Identification of two GDP-6-deoxy-D-lyxo-4-hexulose reductases synthesizing GDP-D-rhamnose in Aneurinibacillus thermoaerophilus L420-91T". J. Biol. Chem. 276 (8): 5577–83. doi: 10.1074/jbc.M010027200 . PMID   11096116.
• Mulichak AM, Bonin CP, Reiter WD, Garavito RM (2002). "Structure of the MUR1 GDP-mannose 4,6-dehydratase from Arabidopsis thaliana: implications for ligand binding and specificity". Biochemistry. 41 (52): 15578–89. CiteSeerX   10.1.1.416.8585 . doi:10.1021/bi0266683. PMID   12501186.