# GDP-mannose 4,6-dehydratase
**GDP-mannose 4,6-dehydratase** (GMD, EC 4.2.1.47) is an enzyme that converts GDP-α-D-mannose to GDP-4-dehydro-α-D-rhamnose (also called GDP-4-keto-6-deoxy-D-mannose) with the release of water, and it forms the first step in the biosynthesis of GDP-D-rhamnose and GDP-L-fucose[1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html). It belongs to the short-chain dehydrogenase/reductase (SDR) enzyme family, whose members share homologous structures and a conserved catalytic triad of Lys, Tyr, and Ser/Thr residues[1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html). In humans the enzyme is encoded by the GMDS gene and uses NADP+ as a cofactor[2](https://www.ncbi.nlm.nih.gov/gene?LinkName=omim_gene&from_uid=602884).
| Key fact | Detail |
|---|---|
| Accepted name and EC number | GDP-mannose 4,6-dehydratase, EC 4.2.1.47; systematic name GDP-α-D-mannose 4,6-hydro-lyase (GDP-4-dehydro-α-D-rhamnose-forming)[1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html) |
| Reaction | GDP-α-D-mannose = GDP-4-dehydro-α-D-rhamnose + H2O[1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html) |
| Protein family | Short-chain dehydrogenase/reductase (SDR) family, with a conserved Lys, Tyr, Ser/Thr catalytic triad[1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html) |
| Quaternary structure | Homodimeric in the *E. coli* enzyme, each monomer with an N-terminal Rossmann-fold NADP(H) domain and a C-terminal sugar-nucleotide binding domain[3](https://pubmed.ncbi.nlm.nih.gov/10673432/); a tetrameric bacterial GMD has also been crystallized[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC2286695/) |
| Pathway role | First and regulatory step in de novo GDP-L-fucose biosynthesis; also first step toward GDP-D-rhamnose[3](https://pubmed.ncbi.nlm.nih.gov/10673432/) • [1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html) |
| Regulation | GDP-fucose acts as a competitive inhibitor at the GDP-mannose site, providing feedback inhibition of fucose biosynthesis[3](https://pubmed.ncbi.nlm.nih.gov/10673432/) |
| Human gene | GMDS (Gene ID 2762)[2](https://www.ncbi.nlm.nih.gov/gene?LinkName=omim_gene&from_uid=602884) |
## Reaction and catalytic mechanism
The reaction removes the hydroxyl group at C6 of the mannose moiety and introduces a keto group at C4, converting GDP-mannose into the 4-keto-6-deoxy intermediate[3](https://pubmed.ncbi.nlm.nih.gov/10673432/). The mechanism involves three catalytic steps. First, GDP-mannose is oxidized at C4″ by an NADP+ cofactor tightly bound to the enzyme. Second, water is eliminated from C5″ and C6″ of the resulting GDP-4″-keto-mannose to form a GDP-4″-keto-mannos-5″,6″-ene intermediate. Third, reduction of this intermediate by NADPH at C6″ gives the product and regenerates NADP+ • [5](https://pubs.acs.org/doi/10.1021/acscatal.9b00064). The cofactor therefore mediates an internal hydride transfer from C4 to C6 and is regenerated each cycle[6](https://www.zhb.uni-luebeck.de/epubs/ediss1539.pdf).
**Active-site residues.** In the *E. coli* enzyme, modeling and site-directed mutagenesis identified Thr133, Glu135, Tyr157, and Lys161 as key catalytic residues: threonine substitutes for serine in the serine-tyrosine-lysine triad common to SDR enzymes, and Glu135 functions as the active-site base[3](https://pubmed.ncbi.nlm.nih.gov/10673432/). Replacing Thr133 with valine reduced the enzyme's kcat by over 3000-fold while only modestly affecting substrate and cofactor binding, supporting a critical catalytic role, potentially in a proton shuttle with Tyr157[7](https://www.sciencedirect.com/science/article/pii/S0969212600000885).
**Human enzyme structures.** Four high-resolution crystal structures of human GMD (hGMD) captured the start and end points of the reaction, including the wildtype enzyme with the substrate analog GDP-4″-deoxy-4″-fluoro-mannose (1.94 Å) and with the product GDP-4″-keto-6″-deoxy-mannose (1.76 Å)[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6454399/). These structures, together with molecular dynamics simulations and mutant characterization, showed that concerted acid-base catalysis from only two active-site groups, Tyr179 and Glu157, promotes a syn 1,4-elimination from an enol (not an enolate) intermediate[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6454399/). Each subunit adopts the characteristic SDR fold, with a Rossmann-fold domain for NADP+ binding and an appended GDP-mannose binding domain; a loop from residues 55 to 63 extends into the neighboring subunit and locks down the bound NADP+, so dimer disruption would be needed for cofactor release[8](https://pmc.ncbi.nlm.nih.gov/articles/PMC6454399/).
The basic mechanism appears to be universally used by sugar 4,6-dehydratases[5](https://pubs.acs.org/doi/10.1021/acscatal.9b00064), although different enzymes employ different acid/base residue pairs to achieve the same 4,6-dehydration: an Asp-Lys couple in CDP-glucose 4,6-dehydratase, an Asp-Glu couple in dTDP-glucose and UDP-GlcNAc 4,6-dehydratases, and a single Glu in GMD[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC8987622/).
## Structure
The *E. coli* apo enzyme structure was refined using data to 2.3 Å resolution. GMD functions as a homodimer, with each monomer split into two domains: the bigger N-terminal one, a standard Rossmann fold, holds the NADP(H) cofactor, while the smaller C-terminal one contains the site that binds the sugar nucleotide[3](https://pubmed.ncbi.nlm.nih.gov/10673432/). Each monomer binds one cofactor and one substrate molecule, indicating that both subunits are catalytically competent[3](https://pubmed.ncbi.nlm.nih.gov/10673432/). A crystal structure of a tetrameric GMD from a bacterial GDP-D-rhamnose biosynthetic pathway has also been determined, with conserved residues such as Arg279 hydrogen bonding to both phosphates of the GDP moiety[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC2286695/).
## Role in GDP-fucose biosynthesis
GDP-fucose is the activated sugar donor used by fucosyltransferases to attach fucose to glycans. In the de novo pathway, GMD converts GDP-mannose to GDP-4-keto-6-deoxymannose, which GDP-fucose synthase (the FX protein, encoded by TSTA3 in humans) then converts through epimerization and reduction steps to GDP-fucose[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC5458543/) • [11](https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1587602/full). It is estimated that about 90% of GDP-fucose in mammals is generated by this de novo pathway under ordinary circumstances, with the remainder coming from a salvage pathway that converts free fucose through the actions of fucokinase and GDP-fucose pyrophosphorylase[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC5458543/) • [12](https://febs.onlinelibrary.wiley.com/doi/10.1002/2211-5463.70057).
**Regulation.** GDP-fucose acts as a competitive inhibitor of GMD, binding at the same site as GDP-mannose, which provides a mechanism for feedback inhibition of fucose biosynthesis[3](https://pubmed.ncbi.nlm.nih.gov/10673432/). The human enzyme is likewise subject to feedback inhibition by GDP-fucose, and differential levels of gene expression provide an additional potential mechanism for regulating its activity[13](https://www.sciencedirect.com/science/article/pii/S002192581852545X).
**Medical relevance.** As a component of many glycoconjugates, among them the ABO blood group antigens and the selectin ligand sialyl Lewis X, fucose is medically significant, and disruptions of GDP-fucose metabolism have been connected with leukocyte adhesion deficiency type II (LADII)[3](https://pubmed.ncbi.nlm.nih.gov/10673432/). The human GMD gene was cloned with the aim of understanding the enzymes of this pathway, their role in selectin-mediated cell adhesion, and the LADII defect[13](https://www.sciencedirect.com/science/article/pii/S002192581852545X).
## Occurrence and variants across organisms
The GDP-L-fucose pathway is conserved across all domains of life[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC8987622/). In plants, the MURUS 1 (MUR1) gene of *Arabidopsis thaliana* encodes an isoform of GDP-D-mannose-4,6-dehydratase required for GDP-fucose synthesis, and the phenotypes of MUR1 mutants suggest that GDP-fucose is vital for normal plant development[14](https://doi.org/10.1146/annurev-arplant-083123-075017). In the bacterium *Aneurinibacillus thermoaerophilus* L420-91T, the enzyme is bifunctional, catalyzing both the 4,6-dehydration and the subsequent reduction reaction of EC 1.1.1.281, GDP-4-dehydro-6-deoxy-D-mannose reductase, in GDP-D-rhamnose biosynthesis[1](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html). Beyond fucose and rhamnose, the GDP-4-keto-6-deoxy-D-mannose product can be directed toward other 6-deoxy sugars by different bifunctional epimerase/reductases, such as GDP-6-deoxy-L-gulose synthase[15](https://www.frontiersin.org/articles/10.3389/fmolb.2021.784142/pdf).
## References
1. [EC 4.2.1.47, IUBMB Enzyme Nomenclature](https://iubmb.qmul.ac.uk/enzyme/EC4/2/1/47.html)
2. [GMDS GDP-mannose 4,6-dehydratase [Homo sapiens], NCBI Gene](https://www.ncbi.nlm.nih.gov/gene?LinkName=omim_gene&from_uid=602884)
3. [Somoza JR et al. (2000). Structural and kinetic analysis of Escherichia coli GDP-mannose 4,6 dehydratase. Structure 8(2):123-135. PubMed](https://pubmed.ncbi.nlm.nih.gov/10673432/)
4. [Crystal structure of a tetrameric GDP-D-mannose 4,6-dehydratase from a bacterial GDP-D-rhamnose biosynthetic pathway, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2286695/)
5. [A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase, ACS Catalysis (2019)](https://pubs.acs.org/doi/10.1021/acscatal.9b00064)
6. [Dissertation introduction on GDP-fucose biosynthesis, Universität zu Lübeck](https://www.zhb.uni-luebeck.de/epubs/ediss1539.pdf)
7. [Somoza JR et al., Structural and kinetic analysis of E. coli GMD, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S0969212600000885)
8. [A Parsimonious Mechanism of Sugar Dehydration by Human GDP-Mannose-4,6-dehydratase, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6454399/)
9. [Nucleotide sugar dehydratases: Structure, mechanism, substrate specificity, and application potential, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC8987622/)
10. [Biological functions of fucose in mammals, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5458543/)
11. [Glycosyltransferases: glycoengineers in human milk oligosaccharide synthesis and manufacturing, Frontiers in Molecular Biosciences (2025)](https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2025.1587602/full)
12. [GDP-fucose transporter SLC35C1: a potential regulatory role in cytosolic GDP-fucose and fucosylated glycan synthesis, FEBS Open Bio (2025)](https://febs.onlinelibrary.wiley.com/doi/10.1002/2211-5463.70057)
13. [Molecular Cloning of Human GDP-mannose 4,6-Dehydratase and Reconstitution of GDP-fucose Biosynthesis in Vitro, ScienceDirect](https://www.sciencedirect.com/science/article/pii/S002192581852545X)
14. [Nucleotide Sugar Transporters: Orchestrating Luminal Glycosylation in Plants, Annual Review of Plant Biology](https://doi.org/10.1146/annurev-arplant-083123-075017)
15. [GDP-mannose dehydrogenase/epimerase family review, Frontiers in Molecular Biosciences (2021)](https://www.frontiersin.org/articles/10.3389/fmolb.2021.784142/pdf)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Metabolism and metabolic pathways › Inborn errors of metabolism (biochemical scope) › Carbohydrate and glycosylation pathway defects › Sugar nucleotide biosynthesis and transporter defects*
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