3-isopentenyl pyrophosphate-► 3-3-Dimethylallyl pyrophosphate

Geranyl pyrophosphate

Isopentenyl pyrophosphate

Farnesyl pyrophosphate

Presqualene pyrophosphate NADPH -►

Ubiquinone Haem Squalene

Fig. 3.7 Pathway for the synthesis of squalene from acetyl-CoA.

mitochondria and vacuoles (see Section 4.1.1). Steryl esters, however, are associated with intracellular lipid particles. In mammalian systems sterol synthesis has been located in the endoplasmic reticulum (Reinhart, 1990). In yeast, however, sterol synthesis (at least the early stages) apparently occurs in mitochondria (Shimizu et al., 1973; Trocha & Sprinson, 1976). Clearly, this requires an intracellular transport system which must link the sites of synthesis of sterols with those of eventual deposition (possibly with the intermediary of esterification in lipid particles).

Alternatively, distinct biosynthetic pathways may provide sterols in individual cellular compartments. Casey et al. (1992) studied the control of the general iso-prenoid biosynthetic pathway in mutant strains of S. cerevisiae. They examined the effects of ergosterol and palmitoleic acid on the key enzyme, 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) which catalyses the conversion of 3-hydroxymethylglutaryl CoA to mevalonate (Fig. 3.7). S. cerevisiae contains two isozymes of HMG-CoA reductase, coded for by the structural genes, HMG1 and HMG2. It was concluded that both isozymes directed equal amounts of carbon into sterol synthesis in haem-competent cells, despite a 57-fold difference in specific activity of the reductases. In mutant strains containing only HMG1 it was discovered that palmitoleic acid was a rate-limiting positive regulator, whereas ergosterol was an inhibitor of sterol production. In strains containing only the HMG2 gene, sterol production was inhibited by palmitoleic acid and to a lesser extent by ergosterol. The reductases were regulated differentially by haem but not by ergosterol and unsatu-

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