Galactose catabolism (Leloir pathway)

The Leloir pathway converts D-galactose to glucose 6-phosphate. A galactose mutarotase supplies alpha-D-galactose, galactokinase phosphorylates it to alpha-D-galactose 1-phosphate, and galactose-1-phosphate uridylyltransferase exchanges UMP with UDP-glucose to give glucose 1-phosphate and UDP-galactose. UDP-glucose 4-epimerase regenerates UDP-glucose from UDP-galactose, so the pathway is catalytic in its UDP-sugar co-substrate, and phosphoglucomutase converts glucose 1-phosphate to glucose 6-phosphate for glycolysis. In bacteria and animals the mutarotase and the epimerase are separate proteins; in yeasts a single bifunctional protein carries an N-terminal UDP-glucose 4-epimerase domain and a C-terminal mutarotase domain. The pathway is distinct from nucleotide-sugar biosynthesis or isolated UDP-galactose epimerization in organisms that lack the galactokinase and uridylyltransferase reactions.

ALIGN (YeastPathways project, 2026-10): S. cerevisiae and S. pombe exemplars were added to every step, the phosphoglucomutase exit step (glucose 1-phosphate to glucose 6-phosphate) was added as the fifth part because the YeastCyc pathway, the PomBase model and the yeast literature (PMID:18779058, PMID:8119301) treat it as the last Leloir enzyme, and the mutarotase step was given an EXACTLY_ONE architecture variant set: a standalone GalM-family mutarotase (bacteria, animals) versus the C-terminal mutarotase domain of the bifunctional yeast GAL10 protein (PMID:14764091). The fused GAL10 proteins classify in the GalE PANTHER subfamily, so the fused variant carries no PANTHER id and is grounded by its representative members; the same proteins are representatives of the shared epimerase step. S. cerevisiae also has two uncharacterized standalone GalM-family proteins (YHR210C, YNR071C) that are not used as exemplars. Galactokinase family membership alone does not establish activity: S. cerevisiae GAL3, in the same PANTHER subfamily as GAL1, is the galactose sensor of the GAL switch rather than the pathway kinase. S. pombe gal1/gal7/gal10 are silenced in wild-type cells (PMID:21075050); S. pombe also has a second UDP-glucose 4-epimerase, uge1, which serves galactosylation on glucose and which the PomBase model places in the Leloir pathway (PMID:19942659); it is not used as a Leloir exemplar here. Galactose uptake (GAL2, S. pombe ght2) and GAL4/GAL80/GAL3 regulation are outside the module. The previous CURATION-only knowledge gap was retired as a curation rather than biological gap; its content is kept here: aldose 1-epimerase and UDP-glucose 4-epimerase families are substrate- and pathway-promiscuous, so a satisfiable Leloir pathway requires galactokinase and galactose-1-phosphate uridylyltransferase in addition to any mutarotase or epimerase candidate (P. putida KT2440 has only GalE and does not satisfy the module). The GO:0033499 label was updated to its current form ("beta-D-galactose ..."). GO-CAM disagreements: YeastPathways YEAST-GALACT-METAB-PWY places all activities in GO:0019388 galactose catabolic process rather than the Leloir-specific GO:0033499, but otherwise agrees. PomBase 6796b94c00002484 includes uge1 and the ght2 transporter and lacks the gal10 mutarotase activity. GROUNDING (2026-11): the epimerase step is grounded at the GalE subfamily PTHR43725:SF47, which holds every exemplar, because the parent family also contains non-epimerase CSP41 proteins and UDP-arabinose 4-epimerases; the P. putida KT2440 GalE exemplar (SF53) was dropped from the step because KT2440 has no galactokinase or uridylyltransferase and so does not run the pathway (it stays in the UDP-sugar biosynthesis module). E. coli Pgm was added as the bacterial phosphoglucomutase exemplar, so every step now has bacterial, animal and yeast members. PAINT ancestral nodes PTN000041817 (GalE, as in the PANTHER grounding batch) and PTN000501426 (phosphoglucomutase) were added. Family-review findings that bear on the module: PAINT gives the plant arabinokinase clade of PTHR10457 the root galactokinase IBA with no loss row, so galactokinase family membership outside SF7 does not establish the activity; and PAINT's IRD withdrawing GO:0033499 from Schizosaccharomyces GalT (PTN008530881) is judged contradicted, since the silenced S. pombe cluster supports galactose growth when expressed (PMID:21075050). A Golgi apparatus IDA on human GALT (PMID:20605918) was found, from the paper's full text, to concern the Golgi marker beta-1,4-galactosyltransferase (B4GALT1), and is removed in the GALT review with a source defect.