Viomycin
Encyclopedia
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.
that encodes 20 open reading frame
s (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 is a summary of the ORFs and their functions.
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 β-ureidoalanine (β-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 β-Uda occurs via VioF, and VioG incorporates L-Cam.
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
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
Capreomycin
Capreomycin is a peptide antibiotic, commonly grouped with the aminoglycosides, which is given in combination with other antibiotics for tuberculosis...
. The tuberactinomycins target bacterial ribosomes, binding RNA and disrupting bacterial protein biosynthesis. It is produced by the actinomycete Streptomyces puniceus, that binds to RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
and inhibits prokaryotic
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
synthesis and certain forms of RNA splicing.
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,β-desaturation of this preliminary structure. It is proposed that the viomycin gene cluster includes 36.3 kb of contiguous DNADNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
that encodes 20 open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
s (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 is a summary of the ORFs and their functions.
- VioA: NRPS (A-PCP-C-A-PCP-C)
- VioH: Type II thioesterase
- VioO: NRPS (A-PCP)-β-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,β-desaturase
- vph: Viomycin phosphotransferase
- VioD: Capreomycidine synthase
- VioK: Ornithine cyclodeaminaseOrnithine cyclodeaminaseIn enzymology, an ornithine cyclodeaminase is an enzyme that catalyzes the chemical reactionHence, this enzyme has one substrate, L-ornithine, and two products, L-proline and NH3....
- VioQ: Capreomycidine hydroxylase
- VioE: Permease
- VioL: Carbamoyltransferase
- VioR: Transcriptional regulator
- VioF: NRPS (A-PCP-C)
- VIoM: NRPS (C)-β-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 biosynthesisBiosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of viomycin using NRPS-catalyzed peptide synthesis. There are five modules
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
for cyclic pentapeptide biosynthesis, including one that lacks an adenylation
Adenylation
Adenylylation is a posttranslational modification that can occur to molecules such as tyrosine residues. Adenylylation involves a phosphodiester bond between a hydroxyl group of the molecule undergoing adenylylation and the phosphate group of the adenosine monophosphate nucleotide Adenylylation is...
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
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
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 β-ureidoalanine (β-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 β-Uda occurs via VioF, and VioG incorporates L-Cam.
Post-modification
After α,β-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 β-lysine, VioO, and VioM, and carbamoylation of the β-amino group, producing β-ureidoalanine (β-Uda) by the carbamoyltransferase homologue VioL.