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Human phosphoglucomutase 1 (PGM1) is an evolutionary conserved enzyme that belongs to the ubiquitous and ancient α- d -phosphohexomutases, a large enzyme superfamily with members in all three domains of life. PGM1 catalyzes the bi-directional interconversion between α- d -glucose 1-phosphate (G1P) and α- d -glucose 6-phosphate (G6P), a reaction that is essential for normal carbohydrate metabolism and also important in the cytoplasmic biosynthesis of nucleotide sugars needed for glycan biosynthesis. Clinical studies have shown that mutations in the  PGM1  gene may cause PGM1 deficiency, an inborn error of metabolism previously classified as a glycogen storage disease, and PGM1 deficiency was recently also shown to be a congenital disorder of glycosylation. Here we present three crystal structures of the isoform 2 variant of PGM1, both as a free enzyme and in complex with its substrate and product. The structures show the longer N-terminal of this PGM1 variant, and the ligand complex structures reveal for the first time the detailed structural basis for both G1P substrate and G6P product recognition by human PGM1. We also show that  PGM1  and the paralogous gene  PGM5  are the results of a gene duplication event in a common ancestor of jawed vertebrates, and, importantly, that both  PGM1  isoforms are conserved and of functional significance in all vertebrates. Our finding that  PGM1  encodes two equally conserved and functionally important isoforms in the human organism should be taken into account in the evaluation of disease-related missense mutations in patients in the future.

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Structural basis for substrate and product recognition in human phosphoglucomutase-1 (PGM1) isoform 2, a member of the α-d-phosphohexomutase superfamily