Sandbox Reserved 1549: Difference between revisions

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<Structure load='3B96' size='300' frame='true' align='right' caption='' scene='Very Long Chain Acyl-CoA Dehydrogenase'/>

Very long-chain acyl-CoA dehydrogenase (VLCAD) is one of the five members of acyl-CoA dehydrogenases (ACADs). VLCADs assembles the initial, rate limiting step of mitochondrial fatty acid β-oxidation<ref name="Crystal Structure of human very long-chain VLCAD"/>. The VLCAD has ideal chain length specificity in which fatty acyl-CoA has 16 carbons in length<ref name="Crystal Structure of human very long-chain VLCAD"/>. They are long-, medium-, and short-chain acyl CoA dehydrogenase<ref name="Crystal Structure of human very long-chain VLCAD"/>. In addition, the activation of acyl CoA dehydrogenase 9 (ACAD-9) is mostly with unsaturated long-chain acyl-CoAs<ref name="Crystal Structure of human very long-chain VLCAD"/>. Unlike other ACADs, mature VLCAD and ACAD-9 are homodimers of 67-kDa subunit which binds to the inner mitochondrial membrane<ref name="Crystal Structure of human very long-chain VLCAD"/>. VLCAD and ACAD- 9 possess an additional 180 residues on the C-terminal end, and also with other AVCADs, they possess MCAD-like catalytic glutamate<ref name="Crystal Structure of human very long-chain VLCAD"/>. In fact, not only allows longer chain-length substrates to bind, VLCAD prefers them to bind<ref name="Crystal Structure of human very long-chain VLCAD"/>. C-terminal domain of VLCAD has shown to be subjected for binding to the matrix side of the inner mitochondrial membrane<ref name="Crystal Structure of human very long-chain VLCAD"/>. A450P and L462P are human clinical mutants in which located in the C-terminal domain. When these mutants are active and stable, it is reducing the capability to bind the membrane<ref name="Crystal Structure of human very long-chain VLCAD"/>. However, there is no clear hydrophobic patch visible that can interact with the membrane, and <scene name='80/806435/Res446/1'>residues 446-478</scene> are the residue that disordered the VLCAD structure<ref name="Crystal Structure of human very long-chain VLCAD"/>. Due to the proximity of <scene name='80/806435/445/1'>residues both 445 and 479 to the surface</scene>, and it expects that the disordered residues occur at the surface of the molecule<ref name="Crystal Structure of human very long-chain VLCAD"/>.  In addition, there are Gln-95 and Glu-99, in which located in MCAD, they help to form the base of the building cavity<ref name="Crystal Structure of human very long-chain VLCAD"/>. In VLCAD, these residues are called glycine (<scene name='80/806435/Gly/1'>Gly-135 and Gly—139</scene>), in which efficiently open up and deepen the binding pocket<ref name="Crystal Structure of human very long-chain VLCAD"/>.  

 

VLCAD is a mitochondrial inner-membrane-associated protein and is a homodimer of a 71-kDa polypeptide containing 2 mol FAD/mol enzyme <ref name="Souri, M., et al."/>. Both rat and human VLCAD cDNAs encode the entire protein of 655 amino acids, including a 40-amino-acid leader peptide and a 615-amino-acid mature protein <ref name="Souri, M., et al."/>. Three other acyl-CoA dehydrogenases share a high degree of sequence similarity throughout the entire sequences <ref name="Souri, M., et al."/>. VLCAD has a region with a significantly high similarity to other acyl-CoA dehydrogenases at the amino-terminal side, but it has a long tail of approximately 180 amino acid residues at the carboxyl-terminal side, which is not shared with other acyl-CoA dehydrogenases <ref name="Souri, M., et al."/>. Substrate-chain-length specificities of the four acyl-CoA dehydrogenases are different but overlapping <ref name="Souri, M., et al."/>. VLCAD is active toward CoA esters of long-chain and very-long-chain fatty acid <ref name="Souri, M., et al."/>.The overall fold of the N-terminal is about 400 residues of VLCAD is similar to that of the soluble ACADs including medium-chain acyl-CoA dehydrogenase (MCAD) <ref name="Crystal Structure of human very long-chain VLCAD"/>. The novelC-terminal domain forms an  -helical bundle that is positioned perpendicular to the two N-terminal helical domains <ref name="Crystal Structure of human very long-chain VLCAD"/>. The fatty acyl moiety of the bound substrate/product is deeply imbedded inside the protein; however, the adenosine pyrophosphate portion of the C14-CoA ligand is disordered because of partial hydrolysis of the thioester bond and high mobility of the CoA moiety <ref name="Crystal Structure of human very long-chain VLCAD"/>.The location of Glu-422with respect to the C2–C3 of the bound ligand and FAD confirms Glu-422 to be the catalytic base <ref name="Crystal Structure of human very long-chain VLCAD"/>. In MCAD, Gln-95 and Glu-99 form the base of the substrate binding cavity <ref name="Crystal Structure of human very long-chain VLCAD"/>. In VLCAD, these residues are glycines (Gly-175 andGly-178), allowing the binding channel to extend for an additional 12 A ˚ and permitting substrate acyl chain lengths as long as 24 carbons <ref name="Crystal Structure of human very long-chain VLCAD"/>.