The mevalonate pathway in C. elegans

Abstract

The mevalonate pathway in human is responsible for the synthesis of cholesterol and other important biomolecules such as coenzyme Q, dolichols and isoprenoids. These molecules are required in the cell for functions ranging from signaling to membrane integrity, protein prenylation and glycosylation, and energy homeostasis. The pathway consists of a main trunk followed by sub-branches that synthesize the different biomolecules. The majority of our knowledge about the mevalonate pathway is currently focused on the cholesterol synthesis branch, which is the target of the cholesterol-lowering statins; less is known about the function and regulation of the non-cholesterol-related branches. To study them, we need a biological system where it is possible to specifically modulate these metabolic branches individually or in groups. The nematode Caenorhabditis elegans (C. elegans) is a promising model to study these non-cholesterol branches since its mevalonate pathway seems very well conserved with that in human except that it has no cholesterol synthesis branch. The simple genetic makeup and tractability of C. elegans makes it relatively easy to identify and manipulate key genetic components of the mevalonate pathway, and to evaluate the consequences of tampering with their activity. This general experimental approach should lead to new insights into the physiological roles of the non-cholesterol part of the mevalonate pathway. This review will focus on the current knowledge related to the mevalonate pathway in C. elegans and its possible applications as a model organism to study the non-cholesterol functions of this pathway.

Figure 1

Overview of the mevalonate pathway. Circles represent the enzymes listed in Table 1. Red: RNAi causes embryonic lethality; Orange: RNAi causes severe phenotypes; Green: RNAi causes mild phenotypes; and Black: RNAi causes no phenotype. Biosynthetic products written in green are also exogenously supplied by the E. coli diet.

Figure 2

Overview of the coenzyme Q biosynthetic pathway. The key step in the pathway is the condensation reaction of the polyisoprenoid side-chain from the mevalonate pathway with 4-hydroxybenzoate, which is the product of a separate multi-step pathway starting from the precursors tyrosine or phenylalanine. Since these precursors are in excess compared to the polyisoprenoids, the rate of ubiquinol synthesis is determined by the availability of the polyisoprenoid: the conversion of Farnesyl-PP to polyprenyl-pp that is catalyzed by enzyme trans-prenyl transferase is the rate limiting step in the synthesis of ubiquinol. Ubiquinol consists of a modified benzoquinone ring attached to hydrophobic isoprenyl tail that contains 6-10 isoprenyl units depending on species. Doted lines represent additional enzymatic steps in the pathway.

Figure 3

Structure of Dolichol and their function during protein N-glycosylation. (A) Structure of Dolichol, where n is dependent on particular cis-prenyltransferase. Dolichol phosphate is an isoprenoid compound (90-100 carbons total) made from dolichol by phosphorylation. Dolichol phosphate performs important functions in synthesis of N-linked glycoproteins, as illustrated in (B). Dolichol phosphate is the structure upon which the complex oligosaccharide is made before transfer to the target protein. The addition of the first moiety, N-acetylglucosamine from UDP-N-acetylglucosamine, can be blocked by the antibiotic, tunicamycin. After assembly of the oligosaccharide is complete, the carbohydrate structure is transferred from dolichol phosphate to an asparagine residue of a target protein having the sequence Asn-x-Ser/Thr, where × is any amino acid. As also shown in (B), Dolichol phosphate can also act as a carrier of sugars to oligosaccharide chain synthesis assembly; such activated sugars include dolichol-P-mannose and dolichol-P-glucose.