Disease relevance of PIS1

• Expression of the Saccharomyces cerevisiae PIS gene and synthesis of phosphatidylinositol in Escherichia coli [1].

High impact information on PIS1

• These data indicated that the regulation of PIS1 gene expression by zinc depletion was mediated by the zinc-regulated transcription factor Zap1p [2].
• We examined the effects of zinc depletion on the regulation of the PIS1-encoded phosphatidylinositol synthase, the enzyme that catalyzes the formation of phosphatidylinositol from CDP-diacylglycerol and inositol [2].
• The zinc-mediated induction of the P(PIS1)-lacZ reporter gene, Pis1p, and phosphatidylinositol synthase activity was lost in zap1Delta mutant cells [2].
• Analysis of a zrt1Delta zrt2Delta mutant defective in plasma membrane zinc transport indicated that the cytoplasmic levels of zinc were responsible for the regulation of phosphatidylinositol synthase [2].
• However, other enzyme activities, including phosphatidylinositol synthase and phosphatidate phosphatase, were not affected in the cki1Delta eki1Delta mutant [3].

Biological context of PIS1

• Thus, PIS1 gene expression is unique among the phospholipid biosynthetic structural genes because it is uncoupled from the inositol response and regulated in response to the carbon source [4].
• Expression of the yeast PIS1 gene requires multiple regulatory elements including a Rox1p binding site [5].
• However, even modest regulation of PIS1 expression has been shown to affect phosphatidylinositol metabolism and to affect cell cycle progression [6].
• Disruption of the PIS locus in the genome is lethal, indicating that PI is essential for the survival and growth of yeast cells [7].
• Reverse transcription-PCR revealed that at least some PIS1 transcripts include all AUG codons, and their synthesis is probably directed by a second TATA box upstream of the putative TATA box [8].

Anatomical context of PIS1

• PI synthase was highly purified from yeast microsomes after solubilization with Triton X-100 [7].
• This lipid is synthesized from CDP-diacylglycerol and myo-inositol by PI synthase, an enzyme localized in the outer mitochondrial membranes and microsomes in yeast [7].
• Two phospholipid-synthesizing enzymes, namely phosphatidylinositol synthase and sn-1,2-diacylglycerol cholinephosphotransferase, are detected in the Golgi at a specific activity which exceeds that of the endoplasmic reticulum [9].
• CDP-diacylglycerol synthase, phosphatidylinositol synthase, and phosphatidylinositol kinase activities were associated with post-Golgi apparatus secretory vesicles destined for the plasma membrane of Saccharomyces cerevisiae [10].
• In this paper we present evidence that certain enzymes of phospholipid biosynthesis, namely phosphatidylserine and phosphatidylinositol synthase, are enriched in a special microsomal fraction associated with mitochondria, which we named MAM [11].

Associations of PIS1 with chemical compounds

• This is unusual because the amounts and/or activities of other phospholipid biosynthetic enzymes are affected by these precursors, and the promoter of the PIS1 gene contains a sequence resembling the regulatory element that coordinates the inositol-mediated regulation (UASINO) [4].
• We found that expression of the PIS1 gene was reduced when cells were grown in a medium containing glycerol and increased when grown in a medium containing galactose relative to cells grown in a glucose medium [4].
• The glycerol-mediated repression of PIS1 gene expression required both the MCM1 gene and the MCEs, whereas the SLN1 gene was required for full galactose-mediated induction of a PIS1-lacZ reporter gene [4].
• These changes can be attributed to an increase in PIS1-encoded PI synthase activity and a decrease in the activities of several CDP-diacylglycerol pathway enzymes including the CHO1-encoded PS (phosphatidylserine) synthase [12].
• Overexpression of PIS1 did not correct the cellular fatty acid content; however, saturated fatty acids (C(16:0)) accumulated preferentially in phosphatidylinositol, and (wild-type)-like fatty acid composition in phosphatidylethanolamine was restored [13].

Physical interactions of PIS1

• The PIS1 promoter includes sequences (MCEs) that bind the Mcm1 protein [4].

Regulatory relationships of PIS1

• Phosphatidylinositol synthase was not found to be regulated in either wild-type or opi1 cells [14].

Other interactions of PIS1

• PI synthase activity follows the decrease of the CDP-DAG synthase activity, but there is no parallel change in the level of PIS1 mRNA [15].
• This is the first example in yeast of a complete circuit linking a stimulus (carbon source) to gene regulation (PIS1) using a two-component regulator (SLN1) [4].
• We found that transcription of the PIS1 gene was insensitive to inositol and choline and did not require the putative UASINO regulatory sequence or the cognate regulatory genes (INO2 and OPI1) [4].
• These results suggest that enhanced phosphatidylinositol synthesis may account for PIS1 suppression of rsp5 defects [13].
• The PIS1 promoter contains the unusual feature of three ATG codons (ATGs1, 2, and 3) in-frame with three stop codons, located just before the authentic start codon (ATG4) [8].

Analytical, diagnostic and therapeutic context of PIS1

• Direct interaction between glutathione S-transferase (GST)-Zap1p(687-880) and a putative upstream activating sequence (UAS) zinc-responsive element in the PIS1 promoter was demonstrated by electrophoretic mobility shift assays [2].
• Using a PIS1(promoter)-lacZ reporter expression system and site-directed mutagenesis, we investigated the role the "upstream" ATG codons play in modulation of PIS1 expression [8].
• Phosphatidylinositol synthase was constitutive in wild type cells grown in the presence of water-soluble phospholipid precursors as determined by enzyme activity and immunoblotting [16].
• To our knowledge, this is the first report on the molecular cloning and functional analysis of a gene encoding a PtdIns synthase in protozoan parasites [17].

References