红霉素的生物合成与组合生物合成

组合生物合成在筛选和发展新型药物方面日益被生物、化学和医药界所关注.红霉素作为组合生物合成发展的模式化合物一直是人们研究的热点.概述了红霉素的生物合成机制及近年来在此基础上采用组合生物合成获得红霉素衍生物的研究进展,并对此方面存在的问题、应用前景作了展望.     

Biosynthesis of thalicarpine

The incorporation of (±)-, norlaudanosoline, ?nor-reticuline, ?N-methylcoclaurine and ?norlaudanidine into thalicarpine in Cocculus laurifolius DC has been studied and specific utilization of (±)- reticuline is demonstrated. The evidence supports that both the “halves” of thalicapine are derived from reticuline. Parallel feedings of (S)-, and (R)-, reticulines showed that the stereospecifity is maintained in the biosynthesis of thalicarpine from the 1-benzyl-tetrahydroisoquinoline precursor.A double-labelling experiment with (±)-[1-³H, 4′-O¹⁴CH₃] nor-reticuline has shown that the 4′OMe group of a nor-reticuline unit is lost in the biotransformation into thalicarpine. Feeding experiments also revealed that the plants can convert (S)-bolding and (S)-isoboldine into thalicarpine.     

Biosynthesis of isotetrandrine

The incorporation of (±)-coclaurine, (±)-N-methylcoclaurine, didehydro-N-methylcoclaurinium iodide, (+)-(S)-N-methylcoclaurine and (?)-(R)-N-methylcoclaurine into isotetrandrine in Cocculus laurifolius DC has been studied and specific utilization of (±)-, (+)-(S)- and (?)-R-N-methylcoclaurines and didehydro-N-methylcoclaurinium iodide demonstrated. The evidence supports intermolecular oxidative coupline of (+)-(S)- and (?)-(R)-N-methylcoclaurines to form isotetrandrine. Double labelling experiment with (±)-N- [¹⁴C] methyl [1 - ³H] coclaurine demonstrated that the hydrogen atom at the asymmetric centre in N-methylcoclaurine is retained in the bioconversion into isotetrandrine.     

Biosynthesis of Mikrolin

Mikrolin (8) and dechloromikrolin (9) have been shown to exist as tautomeric mixtures in solution. The structures of mono-O-trifluoroacetyl Mikrolin (10) and di-O-acetyl Mikrolin (11) have been elucidated. The products 15 to 23 from reduction of the metabolites 8 9 with Pd/C and Zn in aqueous acetic acid have been identified. The ¹³C-NMR. spectra of Mikrolin (8) and dechloromikrolin (9) and their derivatives have been completely assigned Based on the results of incorporation experiments with sodium [1-¹³C]-, [2-¹³C]- and [1, 2-¹³C]-acetate, a biosynthetic pathway is proposed for Mikrolin (8) .     

The structure and chemistry of pebrolide,desacetylpebrolide and 1-deoxypebrolide,sesquiterpene benzoates from penicillium brevicompactum

The structure of three new drimane sesquiterpenes (1–3) has been established from chemical and spectroscopic evidence and by single crystal X-ray crystallographic analysis of 7. Ring B in the crystal of 7 is in a chair conformation, slightly distorted because of cis fusion to the lactone ring and because three β axial substituents are present. NMR evidence suggests that the preferred conformation in solution is similar.     

Biosynthesis of flavocoenzymes

The biosynthesis of one riboflavin molecule requires one molecule of GTP and two molecules of ribulose 5-phosphate. The imidazole ring of GTP is hydrolytically opened, yielding a 2,5-diaminopyrimidine that is converted to 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione by a sequence of deamination, side chain reduction, and dephosphorylation. Condensation of 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione with 3,4-dihydroxy-2-butanone 4-phosphate obtained from ribulose 5-phosphate affords 6,7-dimethyl-8-ribityllumazine. Dismutation of the lumazine derivative yields riboflavin and 5-amino-6-ribitylamino-2,4(1H,3H)-pyrimidinedione, which is recycled in the biosynthetic pathway. The enzymes of the riboflavin pathway are potential targets for antibacterial agents.     

Biosynthesis of cylindrospermopsin

Studies on the biosynthesis of cylindrospermopsin (1), a potent hepatotoxin associated with the cyanobacterium Cylindrospermopsis raciborskii, indicate that 1 is an acetogenin with guanidinoacetic acid serving as the starter unit of the polyketide chain. Feeding experiments show that C14 and C15 of 1 are derived from C1 and C2 of glycine, respectively, and C4 through C13 arise from five contiguous acetate units attached head to tail. The methyl carbon on C13 originates from the C(1) pool. The starter unit, established by the incorporation of [guanidino-(13)C,alpha-(15)N]-guanidinoacetic acid into N16 and C17 of 1, does not appear to be formed from glycine by known amidination pathways. The origin of the NH-CO-NH segment in the uracil ring is also unknown.     

Biosynthesis of pantothenate

Pantothenate is an essential metabolite for all biological systems, however, the biosynthetic pathway is limited to plants, eubacteria and archaea. This suggests that the pathway is a strong candidate for the discovery of novel antibiotic and herbicidal compounds. The enzymology of this short pathway in both bacteria and plants is discussed in detail. In addition a short survey of studies of the whole pathway, and a discussion of both the metabolism and the transport of pantothenate are included.     

Biosynthesis of tetrapetalones

The biosynthesis of tetrapetalones (tetrapetalones A, B, C, and D) in Streptomyces sp. USF-4727 was studied by feeding experiments with [1-13C] sodium propanoate, [1-13C] sodium butanoate, [carbonyl-13C] 3-amino-5-hydroxybenzoic acid (AHBA) hydrochloride, and [1-13C] glucose, followed by analysis of the 13C-NMR spectra. These feeding experiments revealed that the four tetrapetalones were polyketide compounds constructed from propanoate, butanoate, AHBA, and glucose. The tetrapetalone biosynthetic pathway was also suggested in this study. In this pathway, tetrapetalone A (1) is synthesized by polyketide synthase (PKS) using AHBA as a starter unit, then the side chain of 1 is subjected to acetoxylation to produce tetrapetalone B (2). Additionally, 1 is oxidized and transformed into tetrapetalone C (3). In a similar way, 2 is converted to tetrapetalone D (4). Therefore, the biosynthetic relationship of the four tetrapetalones was indicated.     

Biosynthesis of brevicolline

Conclusions 1. When DL-[2^–14C] tryptophan, sodium [2^–14C] pyrotartrate, sodium [¹⁴/C]-formate, and universally labeled L-[¹⁴C] glutamic acid were introduced through the root system intoCarex brevicollis DC, active brevicolline was obtained.2. Tryptophan and sodium pyrotartrate are precursors of the -carboline moiety of the brevicolline molecule, and sodium formate is a precursor of the N-methyl grouping.3. The introduction of universally labeled L-glutamic acid does not lead to an unambiguous indication of the role of this precursor in the biosynthesis of brevicolline.Khimiya Prirodnykh Soedinenii, Vol. 5, No. 1, pp. 39–43, 1969     

Biosynthesis of phloroglucinol

Substantial concentrations of phloroglucinol were synthesized by Pseudomonas fluorescens Pf-5 expressing the plasmid-localized phlACBDE gene cluster responsible for biosynthesis of 2,4-diacetylphloroglucinol. Expression in Escherichia coli of a single gene in this cluster, P. fluorescens Pf-5 phlD, led to extracellular accumulation of phloroglucinol. Purification of PhlD to homogeneity afforded an enzyme that catalyzed the conversion of malonyl-CoA into phloroglucinol with Km = 5.6 muM and kcat = 10 min-1. Acetylase and deacetylase activities were observed with the catalyzed interconversions of phloroglucinol, 2-acetylphloroglucinol, and 2,4-diacetylphloroglucinol when phlACB was expressed in E. coli. Beyond the mechanistic implications attendant with the identification of an enzyme that catalyzes the conversion of malonyl-CoA into phloroglucinol, PhlD provides the basis for environmentally benign syntheses of phloroglucinol and resorcinol from glucose.