Evolutionary History and Functional Diversification of Phosphomannomutase Genes

Abstract

Phosphomannomutases (PMMs) catalyze the interconversion of mannose-6-phosphate to mannose-1-phosphate. In humans, two PMM enzymes exist--PMM1 and PMM2; yet, they have different functional specificities. PMM2 presents PMM activity, and its deficiency causes a Congenital Disorder of Glycosylation (PMM2-CDG). On the other hand, PMM1 can also act as glucose-1,6-bisphosphatase in the brain after stimulation with inosine monophosphate and thus far has not been implicated in any human disease. This study aims to refine the evolutionary time frame at which gene duplication gave rise to PMM1 and PMM2, and to identify the most likely amino acid positions underlying the proteins' different functions. The phylogenetic analysis using available protein sequences, allowed us to establish that duplication occurred early in vertebrate evolution. In order to understand the molecular basis underlying the functional divergence, conserved and most likely functional divergence-related sites were identified, through the analysis of site-specific evolutionary rates. This analysis indicates that most of the sites known to be important in the homodimer formation and in the catalytic activity are conserved in both proteins. Among those potentially related to functional divergence, two positions (183 and 186 in human PMM1) emerge as the most interesting ones. The residues at these positions have different side-chain conformations in the protein structure in the unbound and bound states, and are highly but differently conserved in PMM1 and in PMM2 proteins. Altogether, these results provide new data into the evolutionary history of PMM1 and PMM2 duplicates and highlight the most probable sites that evolved to distinct functional specificities.

Phosphoglucomutase is absent in Trypanosoma brucei and redundantly substituted by phosphomannomutase and phospho‐N‐acetylglucosamine mutase

“…As previously described, the residues involved in the catalysis are located in the core domain (aa 5–82 and 187–246): D9 (Motif I) corresponds to the Asp that is phosphorylated in the reaction, S45 (motif II) and K187 (Motif III) are involved in the binding of the phosphate, and D9, D11 (Motif I), D206 and D214 (Motif IV) co‐ordinate the Mg 2+ ion (Fig. 7B and C) (Allen and Dunaway‐Mariano, 2004; Quental et al ., 2010). The cap domain contributes the residues involved in substrate recognition (E119, R121, M124, N126, R132, R139, S177), so that the active site is located in the groove at the interface of the core and cap domains (Fig.…”

The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

“…Yet, Val231 is closer than Val129 to the catalytic center of PMM2, Asp12, which is the nucleofile transferring the phosphate from the O6 to O1 of mannose. Val231 is invariant in the PMM2 as well as in PMM1 ortologues, while Val129M is not conserved [23]. …”

Initial diagnosis of the congenital disorder of glycosylation PMM2-CDG (CDG1a) in a 4-year-old girl after neurosurgical intervention for cerebral hemorrhage

“…6 The growing numbers of cases and different subtypes of disease 9 revealed the most common type to be PMM2-CDG, which is characterized by a deficiency in the enzyme phosphomannomutase 2 (PMM2), 1 of 2 enzymes that catalyze the conversion of mannose-6-phosphate to mannose-1-phosphate. 19 Because phosphomannomutase 1 is not able to compensate for PMM2, 19 its dysfunction leads to early disruption of the N-glycan assembly of glycoproteins 5 due to a deficit in guanosine diphosphate-mannose. 4,19 It is still an underdiagnosed autosomal recessive genetic disorder with an approximate incidence of 1:20,000, and there are more than 700 affected patients worldwide.…”

“…19 Because phosphomannomutase 1 is not able to compensate for PMM2, 19 its dysfunction leads to early disruption of the N-glycan assembly of glycoproteins 5 due to a deficit in guanosine diphosphate-mannose. 4,19 It is still an underdiagnosed autosomal recessive genetic disorder with an approximate incidence of 1:20,000, and there are more than 700 affected patients worldwide. The mortality rate reaches up to 25% [4][5][6] in children with PMM2-CDG.…”