Sandbox Reserved 321: Difference between revisions

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=Introduction=
=Introduction=


The enzyme inhA is coded from the inhA gene that is simillar in sequence to the ''[http://en.wikipedia.org/wiki/Salmonella_typhimurium Salmonella typhimurium]''gene which plays a role in fatty acid biosynthesis <ref name ="making drugs for inhA">Sacchettini, James (New Rochelle, NY) 1999 INHA crystals and three dimensional structure United States Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) 5882878 http://www.freepatentsonline.com/5882878.html</ref>. Inha is an NADH dependent trans enoyl-acyl ACP carrier protein that plays a role in the sysnthesis of Mycolic Acid, and is part of a short-chain dehydrogenase/reductase family <ref name ="mech of thioamide drug action">PMID:17227913</ref><ref name ="phosphorylation of inhA">PMID:21143326</ref>.  Mycolic acids are long chain fatty acids that are essential in cell wall formation of the human pathogen ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]''as well as other mycobateria such as ''[http://en.wikipedia.org/wiki/Mycobacterium_leprae Mycobacterium leprae]''<ref name ="TB">PMID2568869:</ref>. Inha has been propsed as the target of the thionamide drugs, ethionamide (ETH)  and isoniazid (INH), which have been used in treatment of mycobacterial infections <ref name ="phosphorylation of inhA">PMID:21143326</ref>.   
The enzyme inhA is coded from the inhA gene that is simillar in sequence to the ''[http://en.wikipedia.org/wiki/Salmonella_typhimurium Salmonella typhimurium]''gene which plays a role in fatty acid biosynthesis <ref name ="making drugs for inhA">Sacchettini, James (New Rochelle, NY) 1999 INHA crystals and three dimensional structure United States Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) 5882878 http://www.freepatentsonline.com/5882878.html</ref>. Inha is an NADH dependent trans enoyl-acyl ACP carrier protein that plays a role in the sysnthesis of [http://en.wikipedia.org/wiki/Mycolic_acid Mycolic Acid], and is part of a short-chain dehydrogenase/reductase family <ref name ="mech of thioamide drug action">PMID:17227913</ref><ref name ="phosphorylation of inhA">PMID:21143326</ref>.  Mycolic acids are long chain fatty acids that are essential in cell wall formation of the human pathogen ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]''as well as other mycobateria such as ''[http://en.wikipedia.org/wiki/Mycobacterium_leprae Mycobacterium leprae]''<ref name ="TB">PMID2568869:</ref>. Inha has been propsed as the target of the thionamide drugs, ethionamide (ETH)  and isoniazid (INH), which have been used in treatment of mycobacterial infections <ref name ="phosphorylation of inhA">PMID:21143326</ref>.   




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<Structure load='2h9i' size='300' frame='true' align='left' caption='Momomeric subunit of inhA' scene='Sandbox_Reserved_321/Structural_progresion/1' />
<Structure load='2h9i' size='300' frame='true' align='left' caption='Momomeric subunit of inhA' scene='Sandbox_Reserved_321/Structural_progresion/1' />


The overall strucuture of the inhA enzyme of ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]''is a that of a homotetramer which is composed of a repeating subunit that consits of a single domain with two substructures that are connected by short loop<ref name ="making drugs for inhA"/><ref name ="crystallographic studies">PMID:17588773</ref>.
The inhA enzyme of ''[http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]'' is a homotetramer composed of a repeating subunit comprised of a single domain with a [http://en.wikipedia.org/wiki/Rossmann_fold Rossmann Fold] in the core that provides a NADH binding site<ref name ="crystallographic studies"/>.  The single domain can be broken down into two substructures that are connected by short peptide loop<ref name ="making drugs for inhA"/><ref name ="crystallographic studies">PMID:17588773</ref>.  


==Substructure 1 of inhA==
==Substructure 1 of inhA==
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=Role in the Mycolic Acid Pathway=
=Role in the Mycolic Acid Pathway=


[[Image:Pathway.png|thumb|right|upright=2|alt=Secondary Structure Succession of inhA. Secondary structure residues are ordered from blue to red.|Secondary structure succession inhA.]]
[[Image:Pathway.png|thumb|right|upright=2|alt=Proposed mechanism.|Formulated mechanism of Mycolic acid synthesis as proposed by  Wilson et al.<ref name ="Drug Induced Alterations">10536008 </ref>.]]
 
 


=Protein Superfamilly=
=Protein Superfamilly=

Revision as of 03:38, 1 April 2011

This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada.
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InhAInhA

by Kelly Hrywkiw

PDB ID 2h9i

Drag the structure with the mouse to rotate
2h9i, resolution 2.20Å ()
Ligands:
Gene: inhA (Mycobacterium tuberculosis)
Activity: [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9
Related: 1zid
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml


Secondary Structure Succession of inhA. Secondary structure residues are ordered from blue to red.
Secondary structure succession inhA.

IntroductionIntroduction

The enzyme inhA is coded from the inhA gene that is simillar in sequence to the Salmonella typhimuriumgene which plays a role in fatty acid biosynthesis [1]. Inha is an NADH dependent trans enoyl-acyl ACP carrier protein that plays a role in the sysnthesis of Mycolic Acid, and is part of a short-chain dehydrogenase/reductase family [2][3]. Mycolic acids are long chain fatty acids that are essential in cell wall formation of the human pathogen Mycobacterium tuberculosisas well as other mycobateria such as Mycobacterium leprae[4]. Inha has been propsed as the target of the thionamide drugs, ethionamide (ETH) and isoniazid (INH), which have been used in treatment of mycobacterial infections [3].


Structure of inhAStructure of inhA

Momomeric subunit of inhA

Drag the structure with the mouse to rotate

The inhA enzyme of Mycobacterium tuberculosis is a homotetramer composed of a repeating subunit comprised of a single domain with a Rossmann Fold in the core that provides a NADH binding site[5]. The single domain can be broken down into two substructures that are connected by short peptide loop[1][5].

Substructure 1 of inhASubstructure 1 of inhA

consists of 6 parallel β strands and 4 α helices interwoven together to form a core α/β structure that contains the n-terminal domain[1]. The first substructure can be further broken down into two sections, the consisting of two β strands and two short α helicies [1]. The first section is connected to the by a β strand that crosses over the two domains, and leads into the second section initiating at the third α helix [1](A-3) is connected by a long loop to a 14 residue β strand that then leads into the fourth α helix [1]. A-4 then leads into a fifth strand β , followed by a 25 residue α helix , and into the final strand β [1].

Substructure 2 of inhASubstructure 2 of inhA

contains the c-terminal region of the molecule and consists of a small β strand , and two α helicies which are conected by a short five residue loop[1]. The C-terminal domain consits of two other α helicies [1].

Physiological FunctionPhysiological Function

Role in the Mycolic Acid PathwayRole in the Mycolic Acid Pathway

Proposed mechanism.
Formulated mechanism of Mycolic acid synthesis as proposed by Wilson et al.[6].


Protein SuperfamillyProtein Superfamilly

ReferencesReferences

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Sacchettini, James (New Rochelle, NY) 1999 INHA crystals and three dimensional structure United States Albert Einstein College of Medicine of Yeshiva University (Bronx, NY) 5882878 http://www.freepatentsonline.com/5882878.html
  2. ↑ Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR Jr, Sacchettini JC. Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med. 2007 Jan 22;204(1):73-8. Epub 2007 Jan 16. PMID:17227913 doi:10.1084/jem.20062100
  3. ↑ 3.0 3.1 Molle V, Gulten G, Vilcheze C, Veyron-Churlet R, Zanella-Cleon I, Sacchettini JC, Jacobs WR Jr, Kremer L. Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis. Mol Microbiol. 2010 Dec;78(6):1591-605. doi:, 10.1111/j.1365-2958.2010.07446.x. Epub 2010 Nov 9. PMID:21143326 doi:10.1111/j.1365-2958.2010.07446.x
  4. ↑ Jmol - a paradigm shift in crystallographic visualization. J. Appl. Cryst. (2010). 43, 1250-1260 doi:https://dx.doi.org/10.1107/S0021889810030256
  5. ↑ 5.0 5.1 Dias MV, Vasconcelos IB, Prado AM, Fadel V, Basso LA, de Azevedo WF Jr, Santos DS. Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis. J Struct Biol. 2007 Sep;159(3):369-80. Epub 2007 May 3. PMID:17588773 doi:http://dx.doi.org/10.1016/j.jsb.2007.04.009
  6. ↑ 10536008

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OCA, Kelly Hrywkiw, Andrea Gorrell
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