The X-ray crystal structures of human alpha-phosphomannomutase 1 reveal the structural basis of congenital disorder of glycosylation type 1a

J Biol Chem. 2006 May 26;281(21):14918-26. doi: 10.1074/jbc.M601505200. Epub 2006 Mar 15.


Congenital disorder of glycosylation type 1a (CDG-1a) is a congenital disease characterized by severe defects in nervous system development. It is caused by mutations in alpha-phosphomannomutase (of which there are two isozymes, alpha-PMM1 and alpha-PPM2). Here we report the x-ray crystal structures of human alpha-PMM1 in the open conformation, with and without the bound substrate, alpha-D-mannose 1-phosphate. Alpha-PMM1, like most haloalkanoic acid dehalogenase superfamily (HADSF) members, consists of two domains, the cap and core, which open to bind substrate and then close to provide a solvent-exclusive environment for catalysis. The substrate phosphate group is observed at a positively charged site of the cap domain, rather than at the core domain phosphoryl-transfer site defined by the Asp(19) nucleophile and Mg(2+) cofactor. This suggests that substrate binds first to the cap and then is swept into the active site upon cap closure. The orientation of the acid/base residue Asp(21) suggests that alpha-phosphomannomutase (alpha-PMM) uses a different method of protecting the aspartylphosphate from hydrolysis than the HADSF member beta-phosphoglucomutase. It is hypothesized that the electrostatic repulsion of positive charges at the interface of the cap and core domains stabilizes alpha-PMM1 in the open conformation and that the negatively charged substrate binds to the cap, thereby facilitating its closure over the core domain. The two isozymes, alpha-PMM1 and alpha-PMM2, are shown to have a conserved active-site structure and to display similar kinetic properties. Analysis of the known mutation sites in the context of the structures reveals the genotype-phenotype relationship underlying CDG-1a.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Aspartic Acid / chemistry
  • Carbohydrate Metabolism, Inborn Errors / genetics*
  • Carbohydrate Metabolism, Inborn Errors / metabolism*
  • Cloning, Molecular
  • Crystallography, X-Ray / methods*
  • Humans
  • Hydrolases / chemistry
  • Magnesium / chemistry
  • Models, Chemical
  • Models, Molecular
  • Molecular Conformation
  • Molecular Sequence Data
  • Phosphotransferases (Phosphomutases) / chemistry*
  • Protein Isoforms


  • Protein Isoforms
  • Aspartic Acid
  • Hydrolases
  • 2-haloacid dehalogenase
  • Phosphotransferases (Phosphomutases)
  • phosphomannomutase
  • Magnesium

Associated data

  • PDB/2FUC
  • PDB/2FUE