Viomycin

Viomycin

File:Viomycin.gif
Systematic (IUPAC) name
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
Clinical data
Routes of administration	Intramuscular injection
Identifiers
CAS Number	32988-50-4
ATC code	none
PubChem	CID 3037981
Chemical data
Formula	C25H43N13O10
Molar mass	685.691 g/mol[[]]

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 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 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 , Streptomyces vinaceus and from Streptomyces lividans 1326 [. 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) 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.

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 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 . 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. 

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.

Post-modification of Viomycin.

Figure 2. Post-modification of Viomycin.

References

tr:Viomisin