2,4 Dienoyl-CoA reductase

2,4 Dienoyl-CoA reductase also known as DECR1 is an enzyme which in humans is encoded by the DECR1 gene which resides on chromosome 8. This enzyme catalyzes the following reactions^[1][2][3]

DECR1 participates in the

Eukaryotic DECR exists in both the

Crystallization of mDECR[7] shows the enzyme provides a network of hydrogen bonds from key residues in the active site to NADPH and the 2,4-dienoyl-CoA which positions the hydride at 3.4 Å to the Cδ, compared with 4.0 Å to the Cβ (not shown). The enolate intermediate discussed earlier is stabilized by residues additional hydrogen bonds to Tyr166 and Asn148. Lys214 and Ser210 (conserved residues in all SDR enzymes) are thought to increase the pKa of Tyr166 and stabilize the transition state.^[7] Additionally, at one end of the active site there is a flexible loop that provides sufficient room for long carbon chains. This likely gives the enzyme flexibility to process fatty acid chains of various lengths. Substrate length for mDECR catalysis is thought to be limited at 20 carbons, at which this very long chain fatty acid is first partially oxidized by pDECR in the peroxisome.^[9]

Enzyme mechanism

Eukaryotic DECR

2,4 Dienoyl-CoA thioester reduction by NADPH to 3-Enoyl CoA occurs by a two-step sequential mechanism via an enolate intermediate.

Prokaryotic DECR

2,4 Dienoyl-CoA Reductase from Escherichia coli shares very similar kinetic properties to that of eukaryotes, but differs significantly in both structure and mechanism. In addition to NADPH, E. Coli DECR requires a set of FAD, FMN and iron–sulfur cluster molecules to complete the electron transfer.^[12] A further distinction is E. Coli DECR produces the final 2-trans-enoyl-CoA without the need for Enoyl CoA Isomerase.^[11] The active site contains accurately positioned Tyr166 that donates a proton to the Cγ after hydride attack at the Cδ, completing the reduction in a single concerted step.^[13] Surprisingly, mutation of the Tyr166 does not eliminate enzyme activity but instead changes the product to 3-trans-enoyl-CoA. The current explanation is that Glu164, an acidic residue in the active site, acts as a proton donor to Cα when Tyr166 is not present.^[14]

Function

DECR is one of three auxiliary enzymes involved in a rate-limiting step of

Mutations in the DECR1 gene may result in 2,4 Dienoyl-CoA reductase deficiency,^[17] a rare but lethal disorder.

Due to its role in fatty acid oxidation, DECR may serve as a therapeutic target for treating non-insulin dependent diabetes mellitus (

• Beta oxidation
• 2,4-dienoyl-CoA reductase 1

References