Disease relevance of HMGCS1

• (iii) The expression product of the cDNA in Escherichia coli has HMG-CoA synthase activity [1].
• In contrast with HMG-CoA synthase, C378G Zoogloea ramigera beta-ketothiolase, which also forms a (13)C NMR-observable covalent acetyl-enzyme species, exhibits no (18)O-induced shift [2].
• A double mutant was constructed in Myxococcus xanthus by deletion of genes involved in leucine degradation and disruption of mvaS encoding the 3-hydroxy-3-methylglutaryl-coenzyme A synthase [3].
• In a cultured human hepatoblastoma cell line, Hep G2, chenodeoxycholic acid (CDCA) induced LDL receptor mRNA levels approximately 4 fold and mRNA levels for HMG-CoA reductase and HMG-CoA synthase two fold [4].
• Alterations which occur during the developmental progression of colonic cancer include changes in chromosome 5, which also carries two genes vital to the biosynthesis and regulation of systemic and cellular cholesterol metabolism, 3-hydroxy-3-methylglutaryl coenzyme A synthase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoA R) [5].

High impact information on HMGCS1

• SRE-1, a conditional enhancer in the promoters for the low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl-coenzyme A synthase genes, increases transcription in the absence of sterols and is inactivated when sterols accumulate [6].
• A cis-acting element necessary for sterol regulation, SRE-1, has previously been identified in the promoters of the low density lipoprotein receptor, hydroxymethylglutaryl (HMG)-CoA reductase, and HMG-CoA synthase genes [7].
• The predominantly basic, hydrophobic, and hydroxylated nature of the residues of this sequence suggests that it is a leader peptide to target HMG-CoA synthase inside mitochondria [1].
• (ii) A 19-amino acid sequence probably corresponding to the catalytic site is highly homologous (90%) to that reported for chicken liver mitochondrial HMG-CoA synthase [1].
• 3-Hydroxy-3-methylglutaryl coenzyme A synthase (hydroxymethylglutaryl-CoA synthase, EC 4.1.3.5) is a negatively regulated enzyme in the synthetic pathway for cholesterol, isopentenyl tRNA, and other isoprenoids [8].

Biological context of HMGCS1

• Localization of the gene encoding 3-hydroxy-3-methylglutaryl-coenzyme A synthase to human chromosome 5 [9].
• Real-time PCR helped validate the downregulation of SREBF1, HMGCS1, FDFT1, and HSD3B4 genes [10].
• Optional exon in the 5'-untranslated region of 3-hydroxy-3-methylglutaryl coenzyme A synthase gene: conserved sequence and splicing pattern in humans and hamsters [8].
• Induction of the HMG-CoA synthase promoter required a binding site for sterol regulatory element binding proteins (SRE-BP), consistent with a key role for these transcription factors in the induction of this gene network [11].
• In conclusion, our data demonstrate that regulation of mitochondrial HMG-CoA synthase gene expression by fatty acids is mediated by PPAR, supporting the hypothesis that PPAR has an important role at the transcriptional level in the regulation of lipid metabolism [12].

Anatomical context of HMGCS1

• The chromosomal localization of human HMG-CoA synthase was determined by examining a panel of human-mouse somatic cell hybrids with the rat cDNA probe [13].
• Analysis of Western blot showed that the new cell line strongly expressed mitochondrial HMG-CoA synthase protein [14].
• We and others have described mutant lines of Chinese hamster fibroblasts that are completely resistant to sterol-mediated repression of transcription of HMG-CoA reductase as well as two other sterol-regulated genes, HMG-CoA synthase and the low density lipoprotein (LDL) receptor [15].
• We have investigated whether selected growth factors and hormones could increase 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA in keratinocytes [16].
• We also analyze a new variation of PTS-2 sequences required to target HMG-CoA synthase and MPPD to peroxisomes [17].

Associations of HMGCS1 with chemical compounds

• Approximately 9-fold increases in both HMG-CoA synthase mRNA mass and synthase mRNA activity were observed when control diets were supplemented with cholestyramine and mevinolin [13].
• Transfection of the ketogenic mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase cDNA into Mev-1 cells corrects their auxotrophy for mevalonate [14].
• Treatment of the human monocytic leukemia cell line THP-1 with phorbol esters led to 2--7-fold increases in mRNA concentrations for the three cholesterogenic enzymes, farnesyl pyrophosphate synthetase, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and HMG-CoA synthase within 5 h [18].
• The increases in HMG-CoA synthase and HMG-CoA reductase mRNAs were maximal after treatment of THP-1 cells with 10 micrograms/ml A23187 for 3 h [19].
• Oleate decreased levels of the mature sterol regulatory element-binding proteins SREBP-1 and -2 and HMG-CoA synthase mRNA [20].

Regulatory relationships of HMGCS1

• Multiple DNA elements for sterol regulatory element-binding protein and NF-Y are responsible for sterol-regulated transcription of the genes for human 3-hydroxy-3-methylglutaryl coenzyme A synthase and squalene synthase [21].
• The involvement of multiple responsive elements in the transcription of HMG CoA synthase and squalene synthase seems to induce a higher level of sterol-dependent regulation (3.5 to 5. 8-fold) compared with that of the SREBP-2 promoter, which contains a single pair of SRE motif and CCAAT box (1.8 to 2.6-fold) [21].
• A critical role for cAMP response element-binding protein (CREB) as a Co-activator in sterol-regulated transcription of 3-hydroxy-3-methylglutaryl coenzyme A synthase promoter [22].

Other interactions of HMGCS1

• The mRNA expression of HMG-CoA synthase and reductase, long-chain acyl-CoA synthase and transglutaminase also peaked after 24h, but maximal induction was observed already at 0.00075% SLS [23].
• LDL-receptor, HMG-CoA reductase, and HMG-CoA synthase mRNAs were significantly decreased by cafestol (-18%, -20%, and -43%, respectively) [24].
• Most stimuli that regulate HMG-CoA reductase and LDL receptor mRNA levels also regulate, in parallel, HMG-CoA synthase and farnesyl pyrophosphate (FPP) synthetase [25].
• We conclude that YY1 inhibits the transcription of specific SREBP-dependent genes and that, in the case of the HMG-CoA synthase gene, this involves displacement of nuclear factor Y from the promoter [26].
• The inhibitor had no effect on other sulfhydryl containing enzymes of lipid synthesis such as HMG-CoA synthase, HMG-CoA reductase, and fatty acid synthase [27].

Analytical, diagnostic and therapeutic context of HMGCS1

• Northern blotting was used to demonstrate that 10 microg per ml insulin and 0.1 microg per ml epidermal growth factor both increased steady-state levels of 3-hydroxy-3-methylglutaryl coenzyme A synthase mRNA by 2.5 and 6-fold, respectively [16].
• Messenger RNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, HMG-CoA synthase, and low density lipoprotein (LDL) receptor were quantified in resting and mitogen-stimulated T lymphocytes by nuclease protection assay [28].

References