Evolutionary History and Functional Diversification of Phosphomannomutase Genes |
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Authors: | Rita Quental Ana Moleirinho Luísa Azevedo António Amorim |
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Institution: | (1) Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Rua Dr. Roberto Frias, s/n 4200-465 Porto, Portugal;(2) FCUP, Faculty of Sciences, University of Porto, Porto, Portugal |
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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. |
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