Biosynthesis of naphthomycin A in Streptomyces collinus

Abstract

The biosynthesis of naphthomycin A (1) in Streptonzyces collirt~rs was studied in feeding experiments with single and multiple I3c-labeled precursors followed by I3c NMR analysis of the labeling and I3c-l3c coupling patterns in the product. The results indicate that 1 is assembled via the polyketide pathway from 3-amino-5-hydroxybenzoic acid (2) as the starter unit (mC7N unit) plus seven propionate and six acetate chain extension units. 2 is synthesized via the shikimate pathway by a process that attaches the nitrogen to the carbon derived from C1 of erythrose 4-phosphate, consistent with a new branch of the shikimate pathway recently discovered to operate in the biosynthesis of the mC7N unit of rifamycin B.JONATHAN P. LEE, SHFNG-WAN TSAO, CHING-JER CHANG, XIAN-GUO HE et HBINZ G. FLOSS. Can. J. Chem. 72, 182 (1994).On a CtudiC la biosynthkse de la naphtomycine A (1) dans le Srrepromyces collinus en prockdant B des expkriences au cours desquelles on a foumi des pricurseurs comportant des marqueurs au I3C simples ou multiples alors que l'on a suivi le marquage par une analyse RMN du I3c et par les patrons de couplage I3C-13C dans 1e produit. Les rCsultats indiquent que le produit 1 s'assemble par le biais d'une voie impliquant la formation d'un polycCtide B partir de l'acide 3-amino-5-hydroxybenzoi'que (2) (unit6 mC7N) et des sept unites propioniques et six chaines acCtiques agissant comme extensions. Le composC 2 est synthCtisC par une voie impliquant l'acide shikimique, par un processus que attache un azote au carbone dCrivC du C14-phosphate d'Crythrose; ceci est en accord avec une nouvelle branche de la voie shikimique d6couverte rCcemment et qui est impliquCe dans la biosynthkse de l'unit6 mC7N de la rifamycine B.[Traduit par la rCdaction] Naphthomycin A (I), first isolated from Streptomyces collinus Tii 105 by Balerna et al. (I), is a naphthalenic ansamycin (2, 3) antibiotic that contains an unusually large number of carbon atoms, 23, in its ansa chain. Its constitutional formula was first proposed by Williams (4) and later revised by Rinehart and coworkers (5). The structure was subsequently confirmed by X-ray crystallography, which, together with chemical degradations, also established the absolute configuration (6). Naphthomycin A co-occurs with a number of congeners (1,7,8) and is structurally related to actamycin (8, 9) and the naphthoquinomycins (10). Unlike other ansamycins, 1 is active against Gram-positive bacteria and its mode of action is different from that of other naphthalenic ansamycins, which generally inhibit bacterial RNA polymerase. Its action is antagonized by vitamin K and by sulfhydryl compounds like cysteine (1).In this paper we report the results of studies on the biosynthesis of naphthomycin A that show that its formation probably follows a pathway similar to that previously demonstrated for rifarnycin S (1 1-13), geldanamycin (14, 15), actamycin (9, 16), and ansatrienin (13,17,18 Results and discussionThe origin of the carbon framework of both the naphthoquinoid nucleus and the macr...

The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC7N units in ansamycin and mitomycin antibiotics: a review

“…Later work has repeatedly confirmed the specific role of AHBA as precursor of the mC 7 N unit of various other compounds. [34][35][36][37][38][39] The biosynthetic question then raised was how AHBA was formed by a route that is related to the shikimate pathway. An important issue was whether the nitrogen of AHBA was attached to the carbon corresponding to C-3 or C-5 of shikimate.…”

“…Subsequent work in other systems also confirmed the site of attachment of the nitrogen. 26,37 On the basis of the mitomycin work, Hornemann et al 21 proposed 3,4-dideoxy-4-amino-D-arabino-seduheptulosonic acid 7-phosphate (amino-DAHP), which he hypothesized to arise from DAHP, as the specific precursor of the mC 7 N unit. We subsequently modified this hypothesis based on a report by the group of Jiao 41 that the nitrogen of rifamycin is derived from the amide nitrogen of glutamine.…”

The biosynthesis of shikimate metabolites

“…Continuing these studies, effort has been made to identify the point of divergence from the common shikimate pathway.ls6 An early demonstrated intermediate is the dihydroxydiene (1 86), but this might arise in several ways, namely, dehydration of shikimate, loss of phosphoric acid from shikimate 3-phosphate, or loss of pyruvate from chorismate (Scheme 52). Labelled [2,6,10, 10-2H,]chorismate was fed to Streptornyces collinus, a producer of ansatrienin A (188), and to Alicyclobacillus acidocaldarius, which synthesizes w-cyclohexylundecanoic acid (189). Since labelled shikimic acid is known to be transformed into labelled cyclohexanecarboxylic acid as shown in Scheme 53 (see Ref.…”

Biosynthesis of ansatrienin (mycotrienin) and naphthomycin

“…1) [1]. Feeding experiments with rifamycin (produced by Amycolatopsis mediterranei ), ansatrienin [2] and naphthomycin [3] (produced by Streptomyces collinus ) have demonstrated that the polyketide chain of these antibiotics is assembled from acetate and propionate units in a manner typical of that catalyzed by a multifunctional type I polyketide synthase [4]. The starter unit for these antibiotics is 3‐amino‐5‐hydroxybenzoic acid (AHBA) derived by the newly discovered aminoshikimate pathway, a process which parallels the initial steps of the shikimate pathway (Fig.…”