Tabtoxine- 3-lactam

Both compounds inhibit glutamine synthetase, which is necessary for the production of glutamine and for ammonia detoxification. Plants that are exposed to glufosinate have reduced glutamine and increased ammonia levels in their tissues, which stops photosynthesis and results in death within a few days. Other natural products (e.g. tabtoxine- -lactam, oxetin, and methionine sufoximine) are known to have this mode of action, but they have not been developed as commercial products. 

Tabtoxin J is a dipeptide exotoxin produced by Pseudomonas tabaci, the organism responsible for the wildfire disease of tobacco plants [141]. When hydrolyzed by peptidase, in vivo, this exotoxin releases tabtoxinine-p-lactam K, which inhibits Glutamine synthetase of the photorespiratory nitrogen cycle, causing chlorosis and death of tobacco plants [142]. 

The nucleophile in the side chain will attack the carbonyl group of the lactam and, in the course of the ring enlargement, the atom 1 acts as an internal leaving group. The first example in Scheme VI/19 is tabtoxin (VI/90). 

This compound undergoes a translactamization reaction to give the non-toxic isotabtoxin (VI/91) at room temperature and neutral pH with a half-life of about one day [77] [78] [79]. Inactivation of tabtoxin is even quicker in either acid or base [80]. (The driving force of this conversion seems to be the change to a less strained molecule). The transformation of the /1-lactam to the five-mem-bered VI/95 (by heating in anisol) is another example of this type and includes... 

Baldwin and co-workers have used a nitroso Diels-Alder reaction as a key step in total synthesis of tabtoxin (17), a metabolite causing leafspot disease in tobacco.41 This group has also prepared tabtoxinine /3-lactam (18), the active principle generated by in vivo enzymatic hydrolysis of 17. 

Historically thought to be the active toxin itself, tabtoxin is a precursor that must undergo hydrolysis by a peptidase to yield the biologically active form of a mono-cyclic p-lactam antibiotic (BLA) that is produced by several pathovars and isolates of Pseudomonas syringae, namely tabtoxinin-p-lactam, whose structure is 28 and was isolated in 1978 (Figure 4.12) [43]. 

Figure 4.12 Structure of tabtoxin 27, tabtoxinin-p-lactam 28, and the tabtoxin C-labeling pattern from the incorporation of L-[mef/tyZ- C]methionine, L-[l,2- C2]aspartate, L-[3,4- C2]aspartate, rac-[l,2- C2]glycerol, and [l,2- C2]acetate.

Scheme 17 Baldwin s synthesis of tabtoxin and ( )-tabtoxinine- 8-lactam...

Nitroso-Diels-Alder cyclisations have also proved to be useful in this area and in the synthesis of non-carbohydrate natural products, e,g. tabtoxin (29). Tabtoxinine B-lactam (30) has also been prepared using this methodology with cyclisation of (31) and... 

Bacitracin A and valinomycin are involved in the transport of Mn + and K+, respectively (E 2.2). Tabtoxin and Pseudomonas phaseolicola toxin are bacterial phy to toxins (E 5.4). They contain groupings seldom found in natural products (/3-lactame groups, phosphosulfamine groups). 

As stated in Section 3.1, the first members of this class were nocardicins produced by the strains of Noncardia and Streptomyces. Several monocydic P-lactams containing heteroatom substituents were investigated thereafter for antibacterial activity. Naturally occurring monobactams, however, had only weak antibacterial activity. The only currently available monobactam antibiotic is aztreonam. A monocyclic P-lactam tabtoxin (Figure 3.2), which is a dipeptide esrotoxin, is... 

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