The biosynthetic basis of adult lactase deficiency

Abstract

The intestinal brush-border enzyme lactase splits lactose into its component monosaccharides, glucose and galactose. Relative deficiency of the enzyme during adulthood is a common condition worldwide and is frequently associated with symptoms of lactose intolerance. We studied the synthesis and processing of lactase in normal and adult hypolactasic subjects using human intestinal explants in organ culture. Metabolic labeling experiments in our control subjects with [35S]methionine followed by immunoprecipitation, sodium dodecyl sulfate-polyacrylamide-gel electrophoresis, and fluorography demonstrated that newly synthesized lactase is initially recognized as a precursor molecule with a relative molecular weight (Mr) of 205,000. Over the course of several hours most of the labeled lactase was converted to a mature form of 150,000 Mr. Transiently appearing forms of 215,000 and 190,000 Mr were identified and were felt to represent intermediary species generated during intracellular processing. We identified two distinct alterations in lactase biosynthesis accounting for adult hypolactasia. Studies in three deficient subjects demonstrated markedly reduced synthesis of the precursor protein though posttranslational processing appeared identical to normal. Multiple studies in a fourth deficient subject demonstrated synthesis of ample amounts of precursor lactase but reduced conversion to the mature active form of the enzyme.