L-fucose degradation (mammalian non-phosphorylative pathway)

Catabolism of free cytosolic L-fucose to pyruvate and L-lactate by a five-reaction, non-phosphorylative (oxidative) route described biochemically in pig and rabbit liver and kidney and in human. beta-L-Fucose is oxidized by NAD+-dependent L-fucose dehydrogenase (HSD17B14) to L-fucono-1,5-lactone, which rearranges non-enzymatically to L-fucono-1,4-lactone; a lactonase that has not been molecularly identified in mammals hydrolyses the lactone to L-fuconate; L-fuconate dehydratase (ENOSF1, the rTS-gamma isoform) forms 2-keto-3-deoxy-L-fuconate; an NAD+-dependent 2-keto-3-deoxy-L-fuconate 4-dehydrogenase (BDH2 is the leading candidate) forms 2,4-diketo-3-deoxy-L-fuconate; and an unidentified hydrolase cleaves this to pyruvate and L-lactate. Two of the five steps therefore have no assigned gene and a third has a candidate whose physiological role is unsettled. The route is chemically analogous to the bacterial non-phosphorylative pathway (Xanthomonas, Burkholderia, Herbaspirillum) and is distinct from the phosphorylative FucI/FucK/FucA route of Escherichia coli, from the salvage of L-fucose to GDP-L-fucose, and from lysosomal release of L-fucose from glycoconjugates. The pathway is not universal in mammals: rats oxidize little L-fucose and rat HSD17B14 has negligible L-fucose dehydrogenase activity.

Boundary. IN: the five cytosolic reactions from beta-L-fucose to pyruvate plus L-lactate (fucose dehydrogenase, fuconolactonase, fuconate dehydratase, 2-keto-3-deoxy-L-fuconate 4-dehydrogenase, 2,4-diketo-3-deoxy-L-fuconate hydrolase). OUT, as separate or upstream/downstream biology: (1) supply of free L-fucose by plasma-membrane uptake (GLUT1/SLC2A1, macropinocytosis) and by lysosomal alpha-L-fucosidases FUCA1/FUCA2 with an unidentified lysosomal efflux route; (2) FUOM L-fucose mutarotase, which equilibrates the anomers for both this pathway and salvage, and whose only mammalian cellular phenotype concerns GDP-L-fucose salvage (PMID:17602138); it is not annotated to GO:0042355 and is not added here; (3) the competing salvage fate FCSK (L-fucokinase) and FPGT (fucose-1-phosphate guanylyltransferase) and de novo GDP-L-fucose synthesis (GMDS/GFUS); (4) downstream metabolism of pyruvate and L-lactate; (5) the bacterial phosphorylative FucI/FucK/FucA pathway, which is absent from mammals. Orphan modelling. The two orphan steps use ANY_WITH_FUNCTION participants with the reaction pinned by Rhea and EC, and a step-level knowledge gap stating the unknown enzyme. FAHD1 has been proposed for the terminal hydrolase on sequence similarity to bacterial FAH-family 2,4-diketo-3-deoxy-L-rhamnonate hydrolases, but it is mitochondrial and has never been assayed on the substrate, so it is not listed as a participant. Regucalcin (RGN, aldonolactonase) and 6-phosphogluconolactonase are discussed as possible secondary fuconolactonases but have not been tested, and are also not listed. The 2-keto-3-deoxy-L-fuconate 4-dehydrogenase step is also modelled with an ANY_WITH_FUNCTION participant, because the native pork-liver enzyme (PMID:1158860) was never sequenced. BDH2 is named as the leading candidate: recombinant human BDH2 is active on 2-keto-3-deoxy-L-fuconate (PMID:38918500), but its better-supported physiological activity is 4-oxo-L-proline reductase (GO:0016617, PMID:35150746), and no loss-of-function or flux evidence links it to fucose catabolism. It is not proposed as a NEW L-fucose catabolic process annotation. Compound identity. RHEA:75191 and RHEA:62376 name the diketo intermediate 2,4-didehydro-3-deoxy-L-rhamnonate (CHEBI:131847), and EC 3.7.1.26 is formally the L-rhamnonate-pathway hydrolase. This is the same compound as 2,4-diketo-3-deoxy-L-fuconate: L-fuconate (6-deoxy-L-galactonate) and L-rhamnonate (6-deoxy-L-mannonate) differ only in configuration at C2 and C4, and in the 2,4-diketo-3-deoxy acid C2, C3 and C4 are no longer stereocentres, leaving only C5, which the two share. The rhamnonate-named Rhea and EC entries therefore describe the fucose-pathway reaction. Ontology gaps (not biological gaps). GO has no molecular-function terms for L-fucono-1,4/1,5-lactonase (EC 3.1.1.120; RHEA:75219, RHEA:75223), 2-keto-3-deoxy-L-fuconate 4-dehydrogenase (EC 1.1.1.434; RHEA:75191) or 2,4-diketo-3-deoxy-L-fuconate hydrolase (EC 3.7.1.26; RHEA:62376). These annotons therefore carry a preferred_term and Rhea/EC evidence but no GO id. The fucose dehydrogenase step uses GO:0047834 D-threo-aldose 1-dehydrogenase activity, whose GO xrefs include the L-fucose reaction RHEA:81515. Human gene reviews for HSD17B14, ENOSF1 and BDH2 do not yet exist in this repository; they are the obvious next curation targets. The zebrafish orthologue bdh2 has a review (genes/DANRE/bdh2/bdh2-ai-review.yaml) that adjudicates its 3-hydroxybutyrate dehydrogenase (GO:0003858) and 4-oxoproline reductase (GO:0016617) annotations. No separate module deep-research file was generated; the trigger review PMID:42509779 serves that role.