Zwittermicin A: Difference between revisions

{{Orphan|date=February 2009}}

|IUPACName= 4,8-diamino-N-[1-amino-3-(carbamoylamino)-1-oxopropan-2-yl]-

2,3,5,7,9-pentahydroxynonanamide

| CASNo= 155547-95-8

'''Zwittermicin A''' is an antibiotic that has been identified from the bacterium [[Bacillus cereus]] UW85.<ref name="Zwittermicin">Haiyin, He (April, 1994) "Zwittermicin A, an Antifungal and Plant Protection Agent from Bacillus cereus", Tetrahedron Letters 35 (16) 2499-2502 doi=10.1016/S0040-4039(00)77154-1</ref>. It is a molecule of interest to agricultural industry because it has the potential to suppress plant disease due to its broad spectrum activity against certain gram positive and gram negative [[eukaryotic]] micro-organisms. The molecule is also of interest from a metabolic perspective because it represents a new structural class of antibiotic and suggests a crossover between [[polyketide]] and non-ribosomal peptide biosynthetic pathways. Zwittermicin A is linear aminopolyol<ref name="Synthesis">{{cite journal |author=Rogers EW, Molinski TF |title=Asymmetric synthesis of diastereomeric diaminoheptanetetraols. A proposal for the configuration of (+)-zwittermicin a |journal=Org. Lett. |volume=9 |issue=3 |pages=437–40 |year=2007 |month=February |pmid=17249781 |doi=10.1021/ol062804a |url= |pmc=2729442}}</ref>.

Zwittermycin A [[biosynthesis]] is a hybrid of polyketide and non-ribosomal peptide synthetic pathways. Most likely, all of the synthases are located on one megasynthase much like a type I ketosynthase. Based on mutant studies, the biosynthetic cluster involved in zwittermicin production have been identified and the pathway proposed. The [[gene]]s responsible for the production of zwittermicin A are located on a 16 kb cluster containing nine orfs and a self resistant gene zmaR, a [[gene]] that encodes an [[acylation]] [[enzyme]] that deactivate zwittermicin A.<ref name="Cluster">{{cite journal |author=Stohl EA, Milner JL, Handelsman J |title=Zwittermicin A biosynthetic cluster |journal=Gene |volume=237 |issue=2 |pages=403–11 |year=1999 |month=September |pmid=10521664 |doi= 10.1016/S0378-1119(99)00315-7|url=http://linkinghub.elsevier.com/retrieve/pii/S0378111999003157}}</ref> The hybrid [[synthase]] used in zwittermicin A production utilizes modified extender units such as hydroxymalonyl-ACP, aminomalonyl-ACP and 2,3 diamino propionate. Therefore, many of the genes in the biosynthetic cluster encode for [[enzyme]]s responsible for the synthesis of these extender units used in the hybrid synthase. For example, orf5 encodes ZWA5A, an enzyme that is responsible for the PLP mediated amination that converts L-serine to 2,3 diaminopropionate. It has also been shown that orf5, orf7, orf4 and orf6 participate in the biosynthesis of aminomalonyl-ACP and orf3, orf2 and orf1 synthesize hydroxymalonyl-ACP.<ref name="Related Genes">{{cite journal |author=Zhao C, Luo Y, Song C, ''et al.'' |title=Identification of three Zwittermicin A biosynthesis-related genes from Bacillus thuringiensis subsp. kurstaki strain YBT-1520 |journal=Arch. Microbiol. |volume=187 |issue=4 |pages=313–9 |year=2007 |month=April |pmid=17225146 |doi=10.1007/s00203-006-0196-3 |url=}}</ref>

<br />Genes encoding for the seven component hybrid synthase responsible for the assembly of the backbone is likely located on the largest gene, orf8. Assembly begins by the activation of a serine residue. This is done by tethering the amino acid to a peptidal carrier protein via a non-ribosomal peptide synthase. Subsequently elongation of an activated malonyl unit covalently attached to an acyl carrier protein by a ketosynthase occurs giving the five carbon unit. The next two elongation steps proceed in a similar manner using aminomalonyl and hydroxymalonyl units from a second and third ketosynthase. Finally, condensation of 2,3-diaminopropionate with the carried molecule by a second nonribosomalpeptide synthase produces the zwittermicin A backbone. Attack of ammonia via an amidotransferase enzyme releases the carrier protein. The last step involves a carbomyltransferase enzyme that carbamolates the released molecule giving the final product.<ref name="Genetics">{{cite journal |author=Emmert EA, Klimowicz AK, Thomas MG, Handelsman J |title=Genetics of zwittermicin a production by Bacillus cereus |journal=Appl. Environ. Microbiol. |volume=70 |issue=1 |pages=104–13 |year=2004 |month=January |pmid=14711631 |pmc=321298 |doi= 10.1128/AEM.70.1.104-113.2004|url=http://aem.asm.org/cgi/pmidlookup?view=long&pmid=14711631}}</ref><br />