4FC6

Studies on DCR shed new light on peroxisomal beta-oxidation: Crystal structure of the ternary complex of pDCR

Summary for 4FC6

• Entry DOI: 10.2210/pdb4fc6/pdb
• Related: 4FC7
• Descriptor: Peroxisomal 2,4-dienoyl-CoA reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, HEXANOYL-COENZYME A, ... (4 entities in total)
• Functional Keywords: sdr/rossmann fold, peroxisomal beta-oxidation, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Peroxisome (By similarity): Q9NUI1
• Total number of polymer chains: 4
• Total formula weight: 123310.88

Authors

Hua, T.,Wu, D.,Wang, J.,Shaw, N.,Liu, Z.-J. (deposition date: 2012-05-24, release date: 2012-07-04, Last modification date: 2024-02-28)

Primary citation

Hua, T.,Wu, D.,Ding, W.,Wang, J.,Shaw, N.,Liu, Z.J.
Studies of human 2,4-dienoyl CoA reductase shed new light on peroxisomal beta-oxidation of unsaturated fatty acids
J.Biol.Chem., 287:28956-28965, 2012

PubMed Abstract: Peroxisomes play an essential role in maintaining fatty acid homeostasis. Although mitochondria are also known to participate in the catabolism of fatty acids via β-oxidation, differences exist between the peroxisomal and mitochondrial β-oxidation. Only peroxisomes, but not mitochondrion, can shorten very long chain fatty acids. Here, we describe the crystal structure of a ternary complex of peroxisomal 2,4-dienoyl CoA reductases (pDCR) with hexadienoyl CoA and NADP, as a prototype for comparison with the mitochondrial 2,4-dienoyl CoA reductase (mDCR) to shed light on the differences between the enzymes from the two organelles at the molecular level. Unexpectedly, the structure of pDCR refined to 1.84 Å resolution reveals the absence of the tyrosine-serine pair seen in the active site of mDCR, which together with a lysine and an asparagine have been deemed a hallmark of the SDR family of enzymes. Instead, aspartate hydrogen-bonded to the Cα hydroxyl via a water molecule seems to perturb the water molecule for protonation of the substrate. Our studies provide the first structural evidence for participation of water in the DCR-catalyzed reactions. Biochemical studies and structural analysis suggest that pDCRs can catalyze the shortening of six-carbon-long substrates in vitro. However, the K(m) values of pDCR for short chain acyl CoAs are at least 6-fold higher than those for substrates with 10 or more aliphatic carbons. Unlike mDCR, hinge movements permit pDCR to process very long chain polyunsaturated fatty acids.

PubMed: 22745130
DOI: 10.1074/jbc.M112.385351

Experimental method

X-RAY DIFFRACTION (2.1 Å)