Geranylgeranyltransferase I (GGTase I) catalyzes the transfer of a @entity32004 group from @entity36973 to the @entity1473 -terminal @entity462 of proteins with a motif referred to as a CaaX box (C, @entity462 ; a, usually aliphatic @entity535 ; X, usually L). The alpha and beta subunits of GGTase I from @entity375 are encoded by @entity21682 and @entity48334 , respectively, and each is essential for viability. We are evaluating GGTase I as a potential target for antimycotic therapy of the related @entity375 , @entity5132 , which is the major @entity1 pathogen for disseminated @entity364 . Recently we cloned CaCDC43, the @entity5132 homolog of @entity375 @entity48334 . To study its role in @entity5132 , both alleles were sequentially disrupted in strain CAI4. Null Cacdc43 mutants were viable despite the lack of detectable GGTase I activity but were morphologically abnormal. The subcellular distribution of two GGTase I substrates, Rho1p and Cdc42p, was shifted from the membranous fraction to the cytosolic fraction in the @entity48334 mutants, and levels of these two proteins were elevated compared to those in the parent strain. Two compounds that are potent GGTase I inhibitors in vitro but that have poor antifungal activity, J-109,390 and L-269,289, caused similar changes in the distribution and quantity of the substrate. The lethality of an @entity375 @entity48334 mutant can be suppressed by simultaneous overexpression of @entity34214 and @entity18709 on high-copy-number plasmids (Y. Ohya et al., Mol. Biol. Cell 4:1017, 1991; C. A. Trueblood, Y. Ohya, and J. Rine, Mol. Cell. Biol. 13:4260, 1993). Prenylation presumably occurs by farnesyltransferase (FTase). We hypothesize that Cdc42p and Rho1p of @entity5132 can be prenylated by FTase when GGTase I is absent or limiting and that elevation of these two substrates enables them to compete with FTase substrates for prenylation and thus allows sustained growth.

Geranylgeranyltransferase I of XXXX : null mutants or enzyme inhibitors produce unexpected phenotypes.

@entity1 :: ('9606', 'Species') :: ['human'] @entity32004 :: ('MESH:C016077', 'Chemical') :: ['prenyl'] @entity462 :: ('MESH:D003545', 'Chemical') :: ['cysteine'] @entity535 :: ('CHEBI:33704', 'Chemical') :: ['amino acid'] @entity21682 :: ('853849(Tax:4932)', 'Gene') :: ['RAM2'] @entity34214 :: ('856294(Tax:4932)', 'Gene') :: ['RHO1'] @entity36973 :: ('MESH:C002963', 'Chemical') :: ['geranylgeranyl diphosphate'] @entity5132 :: ('5476', 'Species') :: ['Candida albicans', 'C. albicans'] @entity18709 :: ('850930(Tax:4932)', 'Gene') :: ['CDC42'] @entity364 :: ('MESH:D009181', 'Disease') :: ['fungal infections'] @entity48334 :: ('852722(Tax:4932)', 'Gene') :: ['cdc43', 'CDC43'] @entity375 :: ('4932', 'Species') :: ['yeast', 'Saccharomyces cerevisiae', 'S. cerevisiae'] @entity1473 :: ('CHEBI:46883', 'Chemical') :: ['carboxy']
@entity5132 :: (5476,Species) :: ['Candida albicans']
