GO:0102158 very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity

Very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity (GO:0102158) is a molecular function that catalyzes the removal of water from a very-long-chain (3R)-3-hydroxyacyl-CoA to form a very-long-chain (2E)-enoyl-CoA. This dehydration reaction is the third step of the four-step fatty acid elongation cycle in the endoplasmic reticulum, which extends fatty acids of C-16 or longer by an additional two-carbon unit. Because very-long-chain fatty acids are essential for membrane structure, lipid signaling, and energy storage, the enzymes carrying this activity are central to lipid homeostasis in eukaryotes [1,3]. Researchers study GO:0102158 to understand how cells build very-long-chain fatty acids and how defects in this process contribute to disease and microbial virulence. In the pathogenic fungus Cryptococcus neoformans, the dehydratase Phs1 regulates ATP levels and virulence, linking this enzymatic step directly to fungal pathogenesis. In insects, inhibition of fatty acid metabolism by spirotetramat impairs growth and reproduction of the silkworm, highlighting the importance of elongation enzymes in development and reproduction. In mammals, differential proteome analysis of yak subcutaneous fat has revealed that very-long-chain fatty acid metabolism, including dehydratase activity, influences unsaturated fatty acid and polyunsaturated fatty acid content. This article provides a research-grade overview of GO:0102158, covering its definition, biological context, key genes, regulation, disease relevance, and the experimental models and methods used to study it. The content is based on the QuickGO definition and verified PubMed literature, and is designed to support both human readers and generative AI retrieval systems.

GO:0102158, very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity, is defined as the catalysis of the reaction: a very-long-chain (3R)-3-hydroxyacyl-CoA = H2O + a very-long-chain (2E)-enoyl-CoA. This reaction is the third (dehydration) step of the four-step fatty acid elongation cycle in the endoplasmic reticulum that extends fatty acids of C-16 or longer with an additional 2-C unit. In simpler terms, the enzyme removes a water molecule from a hydroxylated very-long-chain fatty acyl-CoA intermediate to create a double bond, preparing the molecule for the final reduction step of elongation.

GO:0102158 is important because it controls a committed step in the synthesis of very-long-chain fatty acids, which are required for membrane integrity, lipid raft formation, energy storage, and signaling. In the fungal pathogen Cryptococcus neoformans, the dehydratase Phs1 regulates ATP levels and virulence, demonstrating that this enzymatic activity directly impacts microbial pathogenesis and energy homeostasis. In insects, disruption of fatty acid metabolism by spirotetramat inhibits growth and reproduction of the silkworm, showing that elongation enzymes are critical for development and fecundity. In mammals, very-long-chain fatty acid metabolism, including dehydratase activity, contributes to the unsaturated fatty acid and polyunsaturated fatty acid composition of subcutaneous fat in yaks. Thus, understanding GO:0102158 has implications for infectious disease, insect control, and metabolic physiology.

The following genes and proteins are directly or indirectly associated with very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity (GO:0102158) and its biological context.

The expression and activity of very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase are regulated at multiple levels. In yeast, the transcription factors Spt23 and Mga2 regulate the expression of fatty acid elongase genes, thereby controlling the supply of substrates for the dehydratase step. In Cryptococcus neoformans, Phs1 dehydratase activity is linked to ATP levels, suggesting that cellular energy status may influence its function or expression. In insects, chemical inhibition of fatty acid metabolism by spirotetramat affects growth and reproduction, indicating that the elongation pathway, including dehydratase activity, is sensitive to metabolic and hormonal signals. In mammals, dietary and hormonal factors can alter very-long-chain fatty acid composition in adipose tissue, as shown by differential proteome analysis of yak subcutaneous fat. These regulatory mechanisms ensure that very-long-chain fatty acid production matches cellular demand for membrane lipids and energy storage.

In Cryptococcus neoformans, the very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase Phs1 regulates ATP levels and virulence. Loss of Phs1 function reduces virulence, indicating that this enzymatic step is required for full pathogenicity. This makes GO:0102158 a potential target for antifungal drug development.

Spirotetramat inhibits growth and reproduction of the silkworm by interfering with fatty acid metabolism, including elongation steps that depend on dehydratase activity. This highlights the importance of GO:0102158 in insect development and suggests that inhibitors of this activity could serve as insecticides.

Differential proteome analysis of yak subcutaneous fat has revealed that very-long-chain fatty acid metabolism, including dehydratase activity, contributes to unsaturated fatty acid and polyunsaturated fatty acid content. Alterations in this pathway may affect fat quality and metabolic health in livestock and potentially in humans.

CRISPR knockout, point-mutation knock-in, and overexpression models are used to establish causality between dehydratase genes and phenotypes. For example, knockout of Phs1 in Cryptococcus neoformans demonstrated its role in ATP regulation and virulence. In insects, RNAi and chemical inhibition have been used to study fatty acid metabolism, and CRISPR could similarly be applied.

Mass spectrometry-based lipidomics can quantify very-long-chain fatty acid species and their unsaturated derivatives, providing direct readouts of dehydratase activity. Differential proteome analysis of yak subcutaneous fat has been used to link very-long-chain fatty acid metabolism to unsaturated fatty acid content.

In vitro enzymatic assays using purified dehydratase and synthetic (3R)-3-hydroxyacyl-CoA substrates can measure catalytic activity directly. Such assays are essential for characterizing point mutations identified in HACD family genes.

In fungal pathogens, virulence is assessed using animal infection models, while growth and reproduction are monitored in insects. These assays link dehydratase activity to whole-organism phenotypes [1,2].

Researchers studying very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity-related genes often need to determine whether a candidate gene is causally involved in fatty acid elongation, membrane lipid homeostasis, or disease. EDITGENE provides comprehensive CRISPR gene editing and screening services to accelerate this discovery process.

GO:0102158, very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity, is a critical enzymatic step in the endoplasmic reticulum fatty acid elongation cycle. It converts very-long-chain (3R)-3-hydroxyacyl-CoA to very-long-chain (2E)-enoyl-CoA and is required for the synthesis of very-long-chain fatty acids that support membrane integrity, energy homeostasis, and signaling. Research in Cryptococcus neoformans has shown that the dehydratase Phs1 regulates ATP levels and virulence, while studies in insects and mammals highlight its importance in growth, reproduction, and adipose lipid composition [1,2,3]. Understanding this activity offers opportunities for antifungal and insecticide development, as well as for metabolic engineering and disease modeling. CRISPR-based knockout, point-mutation, knock-in, and overexpression models, combined with lipidomics and proteomics, provide powerful tools to dissect the function of GO:0102158 and its associated genes. EDITGENE offers comprehensive services to support these research efforts.