Cisprenyltransferases

Cis-prenyltransferases are enzymes that catalyze the sequential condensation of isopentenyl pyrophosphate (IPP) units onto an allylic pyrophosphate starter to form long-chain polyprenyl diphosphates with cis (Z) double bonds. This stereochemistry distinguishes them from trans-prenyltransferases, which generate trans-configured chains.

In bacteria, undecaprenyl pyrophosphate synthase (UPPS) is the archetypal cis-prenyltransferase. It builds undecaprenyl diphosphate, a lipid carrier that anchors peptidoglycan, teichoic acids, and other cell wall precursors. In eukaryotes and archaea, cis-prenyltransferases participate in dolichol phosphate biosynthesis. The eukaryotic enzyme is a heteromeric complex of dehydrodolichyl diphosphate synthase (DHDDS) and NgBR, which produces dehydrodolichyl diphosphate that is subsequently reduced and phosphorylated to dolichol phosphate, a carrier in N-linked glycosylation.

Reaction and structure: cis-prenyltransferases use IPP as the extender, adding multiple IPP units to an allylic starter substrate and generating a polyprenyl chain with cis double bonds. The final chain length is enzyme-specific and is often determined by the size of the active-site pocket or by associated regulatory subunits. Many members are membrane-associated and form multisubunit complexes.

Significance: Because bacterial UPPS is essential for cell-wall biosynthesis, cis-prenyltransferases are of interest as antibiotic targets. In humans, defects in dolichol biosynthesis can cause congenital disorders of glycosylation, highlighting the importance of cis-prenyltransferase activity for proper protein glycosylation.