Sandbox Reserved 1549

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This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
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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. Three other acyl-CoA dehydrogenases share a high degree of sequence similarity throughout the entire sequences . 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. Substrate-chain-length specificities of the four acyl-CoA dehydrogenases are different but overlapping. VLCAD is active toward CoA esters of long-chain and very-long-chain fatty acid.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"/>.
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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"/>.
== Notes ==
== Notes ==
<references/>
<references/>

Revision as of 05:14, 5 May 2019

This Sandbox is Reserved from May 28 through July 01, 2019 for use in the course Advanced Biochemistry BCHM 4100 taught by Tom Gluick at the Georgia Gwinnett College. This reservation includes Sandbox Reserved 1544 through Sandbox Reserved 1555.
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Contents

A Very Long Chain Acyl-CoA Dehydrogenase

PDB ID 3B96

Drag the structure with the mouse to rotate

You may include any references to papers as in: the use of JSmol in Proteopedia [1] or to the article describing Jmol [2] to the rescue.

Function

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[3]. The VLCAD has ideal chain length specificity in which fatty acyl-CoA has 16 carbons in length[3]. They are long-, medium-, and short-chain acyl CoA dehydrogenase[3]. In addition, the activation of acyl CoA dehydrogenase 9 (ACAD-9) is mostly with unsaturated long-chain acyl-CoAs[3]. Unlike other ACADs, mature VLCAD and ACAD-9 are homodimers of 67-kDa subunit which binds to the inner mitochondrial membrane[3]. 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[3]. In fact, not only allows longer chain-length substrates to bind, VLCAD prefers them to bind[3]. C-terminal domain of VLCAD has shown to be subjected for binding to the matrix side of the inner mitochondrial membrane[3]. 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[3]. However, there is no clear hydrophobic patch visible that can interact with the membrane, and are the residue that disordered the VLCAD structure[3]. Due to the proximity of , and it expects that the disordered residues occur at the surface of the molecule[3]. In addition, there are Gln-95 and Glu-99, in which located in MCAD, they help to form the base of the building cavity[3]. In VLCAD, these residues are called glycine (), in which efficiently open up and deepen the binding pocket[3].

Disease

VLCDA clinical mutation can lead to a disease state. VLCAD is used to break down very long-chain fatty acids, and they are found in food and body’s fat tissue [4]. Fatty acids play a crucial role which provides energy for heart and muscle [3]. Thus, VLCAD deficiency can cause severe neonatal cardiomyopathy and liver failure which occur mostly in adolescence or adulthood [3]. In addition, if the body does not have sufficient amount of VLCAD, it would affect the metabolism of the body [4]. There are several mutation sites that have been found. Mutation R429W is severe in childhood phenotype [3]. on the helix K makes salt-bridge with on helix I [3]. The enzyme is destabilized, and the salt bridge is broken due to the replacing charged residue with the bulky neutral residue [3]. Another mutation site is R416H which is found on the helix J [3]. Both sites,, are located close to the [3]. Site R416H has by making salt bridge and interacts through hydrogen bond [3]. Mutation in R416H causes the problem to the position of helix J [3]. Furthermore, forming a salt bridge with the opposing monomer can affect the dimer interaction [3].

Deficient VLCAD affects 1 person in 40,000 to 120,000 people, thus, it is a very rare diseases [4].


Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

VLCAD is a mitochondrial inner-membrane-associated protein and is a homodimer of a 71-kDa polypeptide containing 2 mol FAD/mol enzyme [5]. 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 [5]. Three other acyl-CoA dehydrogenases share a high degree of sequence similarity throughout the entire sequences [5]. 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 [5]. Substrate-chain-length specificities of the four acyl-CoA dehydrogenases are different but overlapping [5]. VLCAD is active toward CoA esters of long-chain and very-long-chain fatty acid [5].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) [3]. The novelC-terminal domain forms an -helical bundle that is positioned perpendicular to the two N-terminal helical domains [3]. 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 [3].The location of Glu-422with respect to the C2–C3 of the bound ligand and FAD confirms Glu-422 to be the catalytic base [3]. In MCAD, Gln-95 and Glu-99 form the base of the substrate binding cavity [3]. 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 [3].

Notes

  1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 3.22 3.23 3.24 3.25 3.26 3.27 3.28 crystal structure of human very-long-chain acyl-CoA dehydrogenase. The Journal of biological chemistry, 283(14), 9435–9443. doi:10.1074/jbc.M709135200. Retrieved April 30, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431035/
  4. ↑ 4.0 4.1 4.2 VLCAD deficiency - Genetics Home Reference https://ghr.nlm.nih.gov/condition/very-long-chain-acyl-coa-dehydrogenase-deficiency
  5. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Souri.2C_M..2C_et_al.

Reference

1. VLCAD deficiency - Genetics Home Reference - NIH. (2019, April 02). Retrieved April 30, 2019, from https://ghr.nlm.nih.gov/condition/very-long-chain-acyl-coa-dehydrogenase-deficiency

2. McAndrew, R. P., Wang, Y., Mohsen, A. W., He, M., Vockley, J., & Kim, J. J. (2008). Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. The Journal of biological chemistry, 283(14), 9435–9443. doi:10.1074/jbc.M709135200. Retrieved April 30, 2019, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431035/

3. Souri, M., et al. “Relationship between Structure and Substrate-Chain-Length Specificity of Mitochondrial Very-Long-Chain Acyl-Coenzyme A Dehydrogenase.” European Journal Of Biochemistry, vol. 257, no. 3, Nov. 1998, pp. 592–598. EBSCOhost, search.ebscohost.com/login.aspx?direct=true&db=mnh&AN=9839948&site=eds-live&scope=site. from https://http://eds.b.ebscohost.com.libproxyl.ggc.edu/eds/pdfviewer/pdfviewer?vid=2&sid=f09e49a7-ff1c-4d32-b8aa-a3a90cab8b01%40pdc-v-sessmgr06

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