View source for Viomycin

{{Unreferenced|date=November 2006}}
{{drugbox
| IUPAC_name        = <small>IUPAC Name = (S)-3,6-diamino-N-((3S,9S,12S,15S,Z)3((2R,4S)-6-amino-4-hydroxy
-1,2,3,4-tetrahydropyridin-2-yl)- 9,12-bis(hydroxymethyl)2,5,8,11,14-pentaoxo-6-(ureidomethylene)
-1,4,7,10,13-pentaazacyclohexadecan-15-yl)hexanamide </small>
| image             = viomycin.gif
| CAS_number        = 32988-50-4
| ATC_prefix        = none
| PubChem           = 3037981
| C=25|H=43|N=13|O=10
| molecular_weight  = 685.691 g/mol
| legal_AU          =  <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA          =  <!--             / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK          =  <!-- GSL         / P       / POM / CD / Class A, B, C -->
| legal_US          =  <!-- OTC                   / Rx-only  / Schedule I, II, III, IV, V -->
| routes_of_administration = [[Intramuscular]] injection
}}
Viomycin is a member of the tuberactinomycin family, a group of nonribosomal peptide [[antibiotics]] exhibiting anti-[[tuberculosis]] properties. The tuberactinomycin family is an essential component in the drug cocktail currently used to fight infections of  ''Mycobacterium tuberculosis'' .  Viomycin was the first member of the tuberactinomycins to be isolated and identified <ref name=tuberactinomycin>{{cite journal | author=Barkei, J.; Kevany, B.; Felnagle, E.; Thomas, M.  | journal=ChemBioChem. | year=2009 | volume=10 |  pages=366 | pmid=19105177 | title=Investigations into viomycin biosynthesis by using heterologous production in Streptomyces lividans. | issue=2 | doi=10.1002/cbic.200800646 | pmc=2765823 }}</ref>  and was used to treat TB until it was replaced by the less toxic, but structurally related compound, [[capreomycin]].  The tuberactinomycins target bacterial ribosomes, binding RNA and disrupting bacterial protein biosynthesis.  It is produced by the [[actinomycete]] ''Streptomyces puniceus,'' that binds to [[RNA]] and inhibits [[prokaryote|prokaryotic]] [[protein]] synthesis and certain forms of RNA splicing. X-ray crystallography:  B. W. Bycroft,Chem. Commun. 1972, 660.  Confirmed structure: Noda et al. J. Antibiot. 25, 427 (1972).  T. Kitagawa et al. Chem. Pharm. Bull. 20, 2215 (1972).

== Biosynthesis==
The gene cluster for Viomycin has been sequenced from Streptomyces sp. strain ATCC 11861 <ref name=strep_11861>{{cite journal | doi=10.1128/AAC.47.9.2823-2830.2003 | author=Thomas, M.; Chan, Y.; Ozanick, S., | journal= Antimicrob. Agents Chemother.| year=2003 | volume=47 |  pages=2823 | pmid=12936980 | title=Deciphering tuberactinomycin biosynthesis: isolation, sequencing, and annotation of the viomycin biosynthetic gene cluster. | issue=9 | pmc=182626 }}</ref>, Streptomyces vinaceus <ref name=strep_v>{{cite journal | doi= 10.1016/S0378-1119(03)00617-6 | author= Yin, X.; O'Hare, T.; Gould, S.; Zabriskie, M., | journal= Gene| year=2003 | volume=312 |  pages=215 | pmid= 12909358 | title= Identification and cloning of genes encoding viomycin biosynthesis from Streptomyces vinaceus and evidence for involvement of a rare oxygenase. }}</ref> and from Streptomyces lividans 1326 [<ref name=tuberactinomycin>{{cite journal | author=Barkei, J.; Kevany, B.; Felnagle, E.; Thomas, M.  | journal=ChemBioChem. | year=2009 | volume=10 |  pages=366 | pmid=19105177 | title=Investigations into viomycin biosynthesis by using heterologous production in Streptomyces lividans. | issue=2 | doi=10.1002/cbic.200800646 | pmc=2765823 }}</ref>.  It consists of a central cyclic pentapeptide code assembled from [[nonribosomal peptide synthetase ]] (NRPS).  The NRPS contains 4 proteins: VioA, VioF, VioI, and VioG.  These proteins condense and cyclize two molecules of L-2,3-diaminopropionate (L-Dap), two molecules of L-serine (L-Ser), and one molecule of (2S, 3R)-capreomycidine (L-Cam).   After cyclizing these, VioJ catalyzes the α,ß-desaturation of this preliminary structure. It is proposed that the viomycin gene cluster includes 36.3 kb of contiguous [[DNA]] that encodes 20 open reading frames (ORFs) <ref name=strep_11861>{{cite journal | doi=10.1128/AAC.47.9.2823-2830.2003 | author=Thomas, M.; Chan, Y.; Ozanick, S., | journal= Antimicrob. Agents Chemother.| year=2003 | volume=47 |  pages=2823 | pmid=12936980 | title=Deciphering tuberactinomycin biosynthesis: isolation, sequencing, and annotation of the viomycin biosynthetic gene cluster. | issue=9 | pmc=182626 }}</ref> that are involved in the biosynthesis, regulation, and eventual activation viomycin.  In addition to these ORFs, the structure contains the resistance gene vph.  The following table is a summary of the ORFs and their function.

{| class="wikitable" border="1"
|-
! Gene
! Function
! Gene
! Function
! Gene
! Function
|-
| VioA
| NRPS (A-PCP-C-A-PCP-C)
|  VioH
| Type II thioesterase
| VioO
| NRPS (A-PCP)-ß-lysine activation
|-
| VioB
| 2,3-diaminopropionate synthase
| VioI
| NRPS (PCP-C)
| VioP
| Lysine 2,3-aminomutase
|-
| VioC	
| L-Arg hydroxylase	 
| VIoJ	
| 2,3-diaminopropionyl α,ß-desaturase	
| vph	
| Viomycin phosphotransferase
|-
| VioD	
| Capreomycidine synthase
| VioK	
| Ornithine cyclodeaminase	
| VioQ	
| Capreomycidine hydroxylase
|-
| VioE
| Permease
| VioL	
| Carbamoyltransferase
| VioR	
| Transcriptional regulator
|-
| VioF
| NRPS (A-PCP-C)
| VIoM	
| NRPS (C)-ß-lysine transferase
| VIoS
| Viomycin-phosphate phosphatase
|-
| VioG
| NRPS (A-PCP-C/)
| VioN
| MbtH homolog
| VioT
| Transcriptional regulator
|-
|}

=== Synthesis of the backbone ===
The following is the proposed [[biosynthesis]] of Viomycin using  NRPS-catalyzed peptide synthesis. There are five [[Protein domain|modules]] for cyclic pentapeptide biosynthesis, including one that lacks an [[adenylation]] domain (A).  It is therefore proposed that one of the other A domains functions twice.  Additionally, the NRPS subunits are not suspected to function in the order in which their [[genes]] are arranged, a characteristic of Viomycin biosynthesis that is unlike typical NRPS-catalyzed peptide synthesis <ref name=tuberactinomycin>{{cite journal | author=Barkei, J.; Kevany, B.; Felnagle, E.; Thomas, M.  | journal=ChemBioChem. | year=2009 | volume=10 |  pages=366 | pmid=19105177 | title=Investigations into viomycin biosynthesis by using heterologous production in Streptomyces lividans. | issue=2 | doi=10.1002/cbic.200800646 | pmc=2765823 }}</ref>.  The NRPS components function in the order of VioA→VioI→VioF→VioG to account for the incorporation of ß-ureidoalanine (ß-Uda).  The first A domain of VioA creates an L-Dap-PCP intermediate on the first PCP domain.  Meanwhile, the second A domain of VioA loads L-Ser onto the second PCP domain, as well as the PCP of VioI.  The activation of ß-Uda occurs via VioF, and VioG incorporates L-Cam. 

[[File:viomycin_biosynthesisIII.png|none|800px|Domain organization of Viomycin.]]
'''Figure 1.''' Domain Organization of Viomycin.

=== Post-modification ===
After α,ß-desaturation via VioJ, three modifications to the preliminary cyclic structure occur.  Hydroxylation of C-6 in the structure occurs by VioQ, N-acylation of α-amino group using ß-lysine, VioO, and VioM, and carbamoylation of the ß-amino group, producing ß-ureidoalanine (ß-Uda) by the carbamoyltransferase homologue VioL.

[[Image:Post_modificationsII.png|none|800px|Post-modification of Viomycin.]]
'''Figure 2.''' Post-modification of Viomycin.

== References ==
<references/>

[[Category:Polypeptide antibiotics]]


[[tr:Viomisin]]
[[Category:2Fix]]