Details for: HMGCS2

Gene ID: 3158

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: HMGCS2

Ensembl ID: ENSG00000134240

Description: 3-hydroxy-3-methylglutaryl-CoA synthase 2

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • IgA plasma cell CL0000987
    CSI 14.74
    rCSI 15.09%
    PRS 92.7
  • goblet cell CL0000160
    CSI 12.79
    rCSI 12.09%
    PRS 89.15
  • colon goblet cell CL0009039
    CSI 11.46
    rCSI 27.25%
    PRS 92.8
  • colon epithelial cell CL0011108
    CSI 11.19
    rCSI 11.72%
    PRS 89.05
  • transit amplifying cell of colon CL0009011
    CSI 9.02
    rCSI 10.6%
    PRS 91.13
  • enterocyte of epithelium of large intestine CL0002071
    CSI 8.75
    rCSI 45.95%
    PRS 92.82
  • midzonal region hepatocyte CL0019028
    CSI 8.72
    rCSI 20.46%
    PRS 88.91
  • enteroendocrine cell CL0000164
    CSI 6.71
    rCSI 9.17%
    PRS 89.68
  • intestinal epithelial cell CL0002563
    CSI 6.64
    rCSI 6.94%
    PRS 88.95
  • mucous neck cell CL0000651
    CSI 6.43
    rCSI 9.27%
    PRS 93.63
  • intestine goblet cell CL0019031
    CSI 6.15
    rCSI 5.46%
    PRS 88.89
  • hepatic stellate cell CL0000632
    CSI 6.14
    rCSI 22.99%
    PRS 87.18
  • intestinal crypt stem cell of colon CL0009043
    CSI 5.97
    rCSI 44.86%
    PRS 95.19
  • Kupffer cell CL0000091
    CSI 5.84
    rCSI 13.35%
    PRS 92.16
  • nasal mucosa goblet cell CL0002480
    CSI 5
    rCSI 5.8%
    PRS 91.62
  • mucus secreting cell CL0000319
    CSI 4.72
    rCSI 7.49%
    PRS 95.05
  • M cell of gut CL0000682
    CSI 4.64
    rCSI 4.93%
    PRS 93.2
  • renal principal cell CL0005009
    CSI 4.54
    rCSI 11.8%
    PRS 90.56
  • hepatocyte CL0000182
    CSI 4.21
    rCSI 7.53%
    PRS 89.79
  • periportal region hepatocyte CL0019026
    CSI 3.89
    rCSI 15.11%
    PRS 88.15
  • paneth cell CL0000510
    CSI 3.69
    rCSI 5.45%
    PRS 95.79
  • intrahepatic cholangiocyte CL0002538
    CSI 3.59
    rCSI 8.61%
    PRS 91.12
  • epithelial cell of proximal tubule CL0002306
    CSI 3.38
    rCSI 8.25%
    PRS 85.08
  • transit amplifying cell CL0009010
    CSI 3.32
    rCSI 5.08%
    PRS 94.27
  • renal alpha-intercalated cell CL0005011
    CSI 3.22
    rCSI 4.31%
    PRS 94.11
  • BEST4+ enteroycte CL4030026
    CSI 2.95
    rCSI 3.67%
    PRS 90.92
  • foveolar cell of stomach CL0002179
    CSI 2.84
    rCSI 6.06%
    PRS 93.08
  • centrilobular region hepatocyte CL0019029
    CSI 2.73
    rCSI 7.11%
    PRS 87.31
  • enteroendocrine cell of colon CL0009042
    CSI 2.57
    rCSI 12.05%
    PRS 93.16
  • kidney connecting tubule epithelial cell CL1000768
    CSI 2.47
    rCSI 6.26%
    PRS 85.57
  • enterocyte CL0000584
    CSI 2.32
    rCSI 3.74%
    PRS 88.38
  • type L enteroendocrine cell CL0002279
    CSI 2.22
    rCSI 4.16%
    PRS 92.93
  • luminal epithelial cell of mammary gland CL0002326
    CSI 2.21
    rCSI 4.01%
    PRS 95.41
  • colonocyte CL1000347
    CSI 2.06
    rCSI 2.95%
    PRS 89.34
  • retinal pigment epithelial cell CL0002586
    CSI 2.01
    rCSI 3.99%
    PRS 88.03
  • kidney epithelial cell CL0002518
    CSI 1.97
    rCSI 3.76%
    PRS 97.33
  • small intestine goblet cell CL1000495
    CSI 1.97
    rCSI 4.31%
    PRS 93.19
  • enteroendocrine cell of small intestine CL0009006
    CSI 1.88
    rCSI 4.15%
    PRS 93.7
  • paneth cell of epithelium of small intestine CL1000343
    CSI 1.85
    rCSI 5.19%
    PRS 93.87
  • transit amplifying cell of small intestine CL0009012
    CSI 1.7
    rCSI 7.45%
    PRS 94.13
  • club cell CL0000158
    CSI 1.59
    rCSI 2.32%
    PRS 87.17
  • type EC enteroendocrine cell CL0000577
    CSI 1.49
    rCSI 5.28%
    PRS 92.4
  • cholangiocyte CL1000488
    CSI 1.32
    rCSI 7.94%
    PRS 90.43
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.15
    rCSI 3.09%
    PRS 93.08
  • kidney connecting tubule principal cell CL4030018
    CSI 0.76
    rCSI 5.54%
    PRS 90.66
  • paneth cell of colon CL0009009
    CSI 0.48
    rCSI 4.73%
    PRS 94.07
  • enterocyte of epithelium of small intestine CL1000334
    CSI 0.43
    rCSI 6.7%
    PRS 93.56
  • peptic cell CL0000155
    CSI 0.35
    rCSI 3.47%
    PRS 94.77
  • kidney distal convoluted tubule epithelial cell CL1000849
    CSI 0.34
    rCSI 3.55%
    PRS 87.53

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [HMGCS2](/details-gene/3158) (3-hydroxy-3-methylglutaryl-CoA synthase 2) is a protein-coding gene located on chromosome 1p12 that encodes the mitochondrial isoform of HMG-CoA synthase. This enzyme catalyzes the first reaction of the ketogenesis pathway, condensing acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, a crucial step in the production of ketone bodies. Consistent with its central role in energy metabolism, particularly during periods of fasting or low carbohydrate intake, [HMGCS2](/details-gene/3158) shows prominent expression in metabolically active tissues. **Overall**, its significance is highest in various cell types of the gastrointestinal tract, including [goblet cell](/details-cell/CL0000160) and [colon epithelial cell](/details-cell/CL0011108), as well as in [midzonal region hepatocyte](/details-cell/CL0019028), reflecting its critical function in hepatic and extrahepatic ketogenesis. Mutations in this gene are associated with mitochondrial HMG-CoA synthase deficiency ([600234](https://omim.org/entry/600234)), an inherited metabolic disorder characterized by hypoketotic hypoglycemia [[Link](https://doi.org/10.1007/s004390100554)]. ## Cellular Roles and Expression Landscape The expression profile of [HMGCS2](/details-gene/3158) underscores its specialized function in metabolic homeostasis and mucosal biology. **Overall**, the gene's highest significance scores are observed in cells of the digestive system, establishing it as a key marker for metabolic function in this tissue context. It is most significant in secretory and absorptive epithelial cells of the intestine, including [goblet cell](/details-cell/CL0000160), [colon goblet cell](/details-cell/CL0009039), [colon epithelial cell](/details-cell/CL0011108), and [enterocyte of epithelium of large intestine](/details-cell/CL0002071). This strong expression in the colonic epithelium suggests a vital role in local energy production and cellular differentiation, with studies indicating that it is a target of the c-Myc transcription factor and is often downregulated in colon cancer [[Link](https://doi.org/10.1158/1541-7786.mcr-05-0267)]. Beyond the intestine, [HMGCS2](/details-gene/3158) demonstrates high significance in hepatic cells, such as [midzonal region hepatocyte](/details-cell/CL0019028), [hepatic stellate cell](/details-cell/CL0000632), and [Kupffer cell](/details-cell/CL0000091). This is consistent with the liver's primary role as the site of systemic ketone body production. Interestingly, [IgA plasma cell](/details-cell/CL0000987) shows the highest CSI score, which may reflect a specialized metabolic state required for antibody production and function within the gut-associated lymphoid tissue. The collective expression pattern highlights [HMGCS2](/details-gene/3158) as a crucial enzyme not only for systemic ketogenesis in the liver but also for localized metabolic functions within the intestinal mucosa. ## Pathways and Molecular Function The functional annotations for [HMGCS2](/details-gene/3158) firmly place it within the core pathways of lipid and energy metabolism. Its primary molecular function is [hydroxymethylglutaryl-coa synthase activity](/details-go/GO:0004421), which is a rate-limiting step in the [ketone body biosynthetic process](/details-go/GO:0046951). This is corroborated by its involvement in the Reactome pathway for the [synthesis of ketone bodies](/details-pathway/R-HSA-77111). The enzyme is localized to the [mitochondrial matrix](/details-go/GO:0005759), the site of ketogenesis. The gene's activity is integral to broader metabolic networks, including the [metabolism of lipids](/details-pathway/R-HSA-556833) and the [acetyl-coa metabolic process](/details-go/GO:0006084). Its expression is highly responsive to various metabolic and hormonal signals, as indicated by its annotation in processes such as [response to starvation](/details-go/GO:0042594), [cellular response to insulin stimulus](/details-go/GO:0032869), [response to glucagon](/details-go/GO:0033762), and [cellular response to fatty acid](/details-go/GO:0071398). Furthermore, its participation in pathways like [regulation of lipid metabolism by pparalpha](/details-pathway/R-HSA-400206) suggests it is a key downstream effector of transcriptional programs that govern metabolic adaptation. ## Research Directions Analysis of [HMGCS2](/details-gene/3158) reveals its central role in cellular metabolism, with significant implications for both metabolic disease and cancer biology. Research indicates that while highly expressed in differentiated cells of the normal colonic epithelium, its expression is markedly downregulated in colon cancer, suggesting a potential tumor-suppressive role [[Link](https://doi.org/10.1158/1541-7786.mcr-05-0267)]. This metabolic shift away from ketogenesis may be a key event in tumorigenesis. Based on the available data, several testable hypotheses can be proposed: 1. **Hypothesis 1:** The downregulation of [HMGCS2](/details-gene/3158) in colon cancer cells creates a metabolic dependency by shunting acetyl-CoA away from ketogenesis and towards anabolic pathways (e.g., fatty acid synthesis) that support rapid cell proliferation. Restoring its expression would therefore inhibit cancer cell growth. 2. **Hypothesis 2:** The exceptionally high significance of [HMGCS2](/details-gene/3158) in [IgA plasma cell](/details-cell/CL0000987) suggests that local ketone body production by these immune cells in the gut lamina propria serves a paracrine signaling function, potentially modulating the behavior of nearby epithelial cells or T lymphocytes to maintain mucosal homeostasis. A key experiment to test the first hypothesis would be: * To investigate the tumor-suppressive function of [HMGCS2](/details-gene/3158), one could utilize a CRISPR activation (CRISPRa) system to re-express the gene in HMGCS2-low colon cancer cell lines. The impact on cellular bioenergetics could be assessed using Seahorse metabolic flux analysis, while changes in proliferation and survival could be monitored *in vitro* through colony formation assays and *in vivo* using a murine xenograft model. Metabolomic profiling could simultaneously track the redirection of acetyl-CoA into ketone bodies versus other metabolic pathways. Therapeutically, [HMGCS2](/details-gene/3158) itself is not a conventional drug target for inhibition. Instead, its downregulation in certain cancers suggests that strategies aimed at **activation** of the ketogenic pathway or providing exogenous ketone bodies (i.e., a ketogenic diet or ketone ester supplementation) could represent a novel metabolic therapy. This approach might selectively starve cancer cells that have lost the ability to utilize ketones for energy. Conversely, understanding the precise mechanisms of its dysfunction is critical for diagnosing and managing inherited metabolic disorders like HMG-CoA synthase deficiency.

Genular Protein ID: 2924371138

Symbol: HMCS2_HUMAN

Name: Hydroxymethylglutaryl-CoA synthase, mitochondrial

UniProtKB Accession Codes:

P54868 B7Z8R3 D3Y5K6 Q5SZU2 Q6IBF4

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEBI 6 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 18 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 33 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PIR 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 REPRODUCTION-2DPAGE 1 RNAct 1 Reactome 3 RefSeq 3 Rhea 2 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissLipids 1 SwissPalm 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7893153

Title: Molecular cloning and tissue expression of human mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase.

PubMed ID: 7893153

DOI: 10.1006/abbi.1995.1178

PubMed ID: 9305755

Title: Cloning and characterization of the human mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase gene.

PubMed ID: 9305755

DOI: 10.1016/s0378-1119(97)00067-x

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 7851882

Title: Human mitochondrial HMG CoA synthase: liver cDNA and partial genomic cloning, chromosome mapping to 1p12-p13, and possible role in vertebrate evolution.

PubMed ID: 7851882

DOI: 10.1006/geno.1994.1542

PubMed ID: 21952825

Title: Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway.

PubMed ID: 21952825

DOI: 10.1007/s11033-011-1270-8

PubMed ID: 16940161

Title: Ketogenic HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer.

PubMed ID: 16940161

DOI: 10.1158/1541-7786.mcr-05-0267

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 20346956

Title: Crystal structures of human HMG-CoA synthase isoforms provide insights into inherited ketogenesis disorders and inhibitor design.

PubMed ID: 20346956

DOI: 10.1016/j.jmb.2010.03.034

PubMed ID: 11479731

Title: Genetic basis of mitochondrial HMG-CoA synthase deficiency.

PubMed ID: 11479731

DOI: 10.1007/s004390100554

PubMed ID: 11228257

Title: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: clinical course and description of causal mutations in two patients.

PubMed ID: 11228257

DOI: 10.1203/00006450-200103000-00005

PubMed ID: 12647205

Title: Mitochondrial HMG-CoA synthase deficiency: identification of two further patients carrying two novel mutations.

PubMed ID: 12647205

DOI: 10.1007/s00431-002-1110-x

PubMed ID: 16601895

Title: Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency.

PubMed ID: 16601895

DOI: 10.1007/s10545-006-0214-2

PubMed ID: 23751782

Title: New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations.

PubMed ID: 23751782

DOI: 10.1016/j.ejmg.2013.05.008

PubMed ID: 25511235

Title: Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations.

PubMed ID: 25511235

DOI: 10.1007/s10545-014-9801-9

PubMed ID: 29597274

Title: Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients.

PubMed ID: 29597274

DOI: 10.3390/ijms19041010

Sequence Information:

  • Length: 508
  • Mass: 56635
  • Checksum: BD362D631F7C3C80
  • Sequence:
    • MQRLLTPVKR ILQLTRAVQE TSLTPARLLP VAHQRFSTAS AVPLAKTDTW PKDVGILALE 
VYFPAQYVDQ TDLEKYNNVE AGKYTVGLGQ TRMGFCSVQE DINSLCLTVV QRLMERIQLP 
WDSVGRLEVG TETIIDKSKA VKTVLMELFQ DSGNTDIEGI DTTNACYGGT ASLFNAANWM 
ESSSWDGRYA MVVCGDIAVY PSGNARPTGG AGAVAMLIGP KAPLALERGL RGTHMENVYD 
FYKPNLASEY PIVDGKLSIQ CYLRALDRCY TSYRKKIQNQ WKQAGSDRPF TLDDLQYMIF 
HTPFCKMVQK SLARLMFNDF LSASSDTQTS LYKGLEAFGG LKLEDTYTNK DLDKALLKAS 
QDMFDKKTKA SLYLSTHNGN MYTSSLYGCL ASLLSHHSAQ ELAGSRIGAF SYGSGLAASF 
FSFRVSQDAA PGSPLDKLVS STSDLPKRLA SRKCVSPEEF TEIMNQREQF YHKVNFSPPG 
DTNSLFPGTW YLERVDEQHR RKYARRPV