What Is 2-enoyl-CoA hydratase 2

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Last updated: April 15, 2026

Quick Answer: 2-enoyl-CoA hydratase 2 (ECHS2) is a mitochondrial enzyme encoded by the ECHS1 gene in humans, playing a critical role in fatty acid β-oxidation by catalyzing the hydration of 2-trans-enoyl-CoA to 3-hydroxyacyl-CoA. It functions specifically on short- and medium-chain substrates and is essential for energy production in tissues like liver and heart.

Key Facts

ECHS2 is encoded by the ECHS1 gene located on chromosome 10q26.13
Mutations in ECHS1 are linked to a rare metabolic disorder with onset in infancy
The enzyme operates in the mitochondrial matrix, a key site for fatty acid oxidation
It catalyzes the second step in the fatty acid β-oxidation spiral
Deficiency can lead to lactic acidosis and neurological impairment

Overview

2-enoyl-CoA hydratase 2, also known as enoyl-CoA hydratase short-chain 1 (ECHS1), is a mitochondrial enzyme involved in the breakdown of fatty acids. It plays a vital role in the β-oxidation pathway, specifically catalyzing the hydration of 2-trans-enoyl-CoA intermediates to form 3-hydroxyacyl-CoA. This reaction is essential for generating acetyl-CoA, which feeds into the citric acid cycle for ATP production.

Primarily active in high-energy-demand tissues such as the liver, heart, and skeletal muscle, ECHS2 exhibits substrate specificity for short- and medium-chain fatty acids. Its function is tightly coupled with other enzymes in the fatty acid oxidation complex, ensuring metabolic efficiency. Defects in this enzyme disrupt energy homeostasis and are associated with severe clinical outcomes.

Gene location: The ECHS1 gene is located on chromosome 10q26.13 and spans approximately 5,800 base pairs with seven exons.
Protein structure: The mature enzyme consists of 298 amino acids and forms a homodimer, with each subunit contributing to the active site.
Subcellular localization: ECHS2 is imported into the mitochondrial matrix, where it integrates into the multienzyme complex for fatty acid oxidation.
Enzyme specificity: It primarily acts on short- and medium-chain 2-trans-enoyl-CoA substrates, such as crotonyl-CoA (C4).
Reaction type: The enzyme catalyzes a stereospecific hydration reaction, adding water across the double bond to yield L-3-hydroxyacyl-CoA.

How It Works

The catalytic mechanism of 2-enoyl-CoA hydratase 2 involves precise molecular interactions that enable efficient hydration of enoyl-CoA intermediates during fatty acid degradation. Each step is optimized for speed and specificity within the mitochondrial environment.

Substrate binding:2-trans-enoyl-CoA binds to the active site via hydrophobic interactions, positioning the double bond near catalytic residues.
Catalytic residues:Glutamate 144 and glutamate 164 act as proton donors and acceptors, facilitating nucleophilic water attack on the β-carbon.
Reaction mechanism: The enzyme promotes anti-addition of water across the C2=C3 double bond, forming a chiral 3-hydroxy product.
Stereochemistry: The product is exclusively the L-isomer of 3-hydroxyacyl-CoA, compatible with downstream enzymes like HADHA.
Turnover rate: Human ECHS2 has a k_cat of ~120 min⁻¹ for crotonyl-CoA, indicating high catalytic efficiency.
Metabolic coupling: The product feeds directly into the 3-hydroxyacyl-CoA dehydrogenase reaction, maintaining pathway flux.

Comparison at a Glance

Below is a comparison of 2-enoyl-CoA hydratase 2 with related enzymes in fatty acid metabolism:

Enzyme	Gene	Substrate Chain Length	Localization	Disease Association
2-enoyl-CoA hydratase 2	ECHS1	Short- and medium-chain	Mitochondria	Enoyl-CoA hydratase deficiency
2-enoyl-CoA hydratase 1	ECI1	Long-chain	Mitochondria	None well-established
Δ3,Δ2-enoyl-CoA isomerase	ECI2	Unsaturated fatty acids	Mitochondria and peroxisomes	Not directly linked
Acyl-CoA oxidase	ACOX1	Very long-chain	Peroxisomes	Zellweger syndrome
Medium-chain acyl-CoA dehydrogenase	ACADM	Medium-chain	Mitochondria	MCAD deficiency

While all these enzymes participate in fatty acid metabolism, ECHS2 is unique in its strict substrate range and role in early β-oxidation cycles. Its deficiency disrupts energy production more acutely than peroxisomal enzymes due to mitochondrial dependence in vital organs.

Why It Matters

Understanding 2-enoyl-CoA hydratase 2 is crucial for diagnosing and managing rare metabolic disorders and advancing mitochondrial medicine. Its role in energy metabolism makes it a focal point for biochemical research and clinical genetics.

Clinical impact:ECHS1 mutations cause a rare autosomal recessive disorder with symptoms including developmental delay and lactic acidosis.
Diagnostic markers: Elevated propionylcarnitine (C3) and ethylmalonic acid in blood are key diagnostic indicators.
Neurological effects: Deficiency leads to basal ganglia injury, mimicking Leigh syndrome on brain imaging.
Therapeutic challenges: No cure exists; treatment focuses on low-fat diets and carnitine supplementation.
Genetic screening: Over 30 pathogenic variants in ECHS1 have been documented in global databases.
Research applications: ECHS2 is studied in models of mitochondrial dysfunction and neurodegeneration.

As genomic medicine advances, identifying ECHS2-related disorders early improves patient outcomes through targeted management strategies. Continued research may uncover novel therapies for mitochondrial enzyme deficiencies.