Natriuretic peptide pharmacogenetics: Membrane metallo-endopeptidase (MME): Common gene sequence variation, functional characterization and degradation

►Membrane metallo-endopeptidase (MME), also known as neutral endopeptidase 24.11 is involved in the metabolism of natriuretic peptides that play a key role in modulating cardiac structure and function. ►MME was resequenced in three ethnic groups resulting in identification of 90 polymorphisms of which 65 were novel, including 8 nonsynonymous single nucleotide polymorphisms (nsSNPs) of which 7 were not described before. ►The functional effects of the nsSNPs on expressed protein levels and enzyme activity was studied in an in-vitro cell based system leading to the identification of a significant reduction in enzyme activity (21% of wild-type) and immunoreactive protein (29% of wild-type) for the Met73Val variant allozyme ►Proteasome-mediated degradation and autophagy participated in the degradation of the Met73Val allozyme and was associated with increased expression of the chaperone proteins, BiP and GRP94 suggesting protein misfolding, compatible with conclusions based on the MME X-ray crystal structure. ►The Met73Val variant allozyme could have a significant effect on the metabolism of natriuretic peptides.