Novel sterol metabolic network of Trypanosoma brucei procyclic and bloodstream forms

作者：Nes Craigen R; Singha Ujjal K; Liu Jialin; Ganapathy Kulothungan; Villalta Fernando; Waterman Michael R; Lepesheva Galina I; Chaudhuri Minu; Nes W David^*

来源：Biochemical Journal, 2012, 443(1): 267-277.

DOI：10.1042/BJ20111849

• [1-C-13]glucose
• ergosterol biosynthesis
• sterol C24-methyltransferase
• sterol C14-demethylase
• Trypanosoma brucei
• trypanosome

Trypanosoma brucei is the protozoan parasite that causes African trypanosomiasis, a neglected disease of people and animals. Co-metabolite analysis, labelling studies using [methyl-H-2(3)]-methionine and substrate/product specificities of the cloned 24-SMT (sterol C24-methyltransferase) and 14-SDM (sterol C14-demethylase) from T brucei afforded an uncommon sterol metabolic network that proceeds from lanosterol and 31-norlanosterol to ETO [ergosta-5,7,25(27)-trien-3 beta-ol], 24-DTO [dimethyl ergosta-5,7,25(27)-trienol] and ergosterol [ergosta-5,7,22(23)-trienol]. To assess the possible carbon sources of ergosterol biosynthesis, specifically C-13-labelled specimens of lanosterol, acetate, leucine and glucose were administered to T brucei and the C-13 distributions found were in accord with the operation of the acetate mevalonate pathway, with leucine as an alternative precursor, to ergostenols in either the insect or bloodstream form. In searching for metabolic signatures of procyclic cells, we observed that the C-13-labelling treatments induce fluctuations between the acetyl-CoA (mitochondrial) and sterol (cytosolic) synthetic pathways detected by the progressive increase in C-13-ergosterol production (control %26lt;[2-C-13]leucine%26lt;[2-C-13]acetate%26lt;[1-C-13]glucose) and corresponding depletion of cholesta-5,7,24-trienol. We conclude that anabolic fluxes originating in mitochondrial metabolism constitute a flexible part of sterol synthesis that is further fluctuated in the cytosol, yielding distinct sterol profiles in relation to cell demands on growth.

• 出版日期2012-4-1