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21.
Trivedi OA Arora P Vats A Ansari MZ Tickoo R Sridharan V Mohanty D Gokhale RS 《Molecular cell》2005,17(5):631-643
Mycobacterium tuberculosis cell envelope is a treasure house of biologically active lipids of fascinating molecular architecture. Although genetic studies have alluded to an array of genes in biosynthesis of complex lipids, their mechanistic, structural, and biochemical principles have not been investigated. Here, we have dissected the molecular logic underlying the biosynthesis of a virulence lipid phthiocerol dimycocerosate (PDIM). Cell-free reconstitution studies demonstrate that polyketide synthases, which are usually involved in the biosynthesis of secondary metabolites, are responsible for generating complex lipids in mycobacteria. We show that PapA5 protein directly transfers the protein bound mycocerosic acid analogs on phthiocerol to catalyze the final esterification step. Based on precise identification of biological functions of proteins from Pps cluster, we have rationally produced a nonmethylated variant of mycocerosate esters. Apart from elucidating mechanisms that generate chemical heterogeneity with PDIMs, this study also presents an attractive approach to explore host-pathogen interactions by altering mycobacterial surface coat. 相似文献
22.
A series of metallopeptides based on the amino terminal copper/nickel (ATCUN) binding motif have been evaluated as classical inhibitors and catalytic inactivators of both rabbit and human angiotensin-converting enzyme (hACE), and human endothelin-converting enzyme 1 (hECE-1). The cobalt complex [KGHK–Co(NH3)2]2+, where KGHK is lysylglycylhistidyllysine, displayed similar K
I and IC50 values to those found for [KGHK–Cu]+, in spite of the enhanced charge, and so either the influence of charge is offset by the steric influence of the axially coordinated ammine ligands, or binding is dominated by contributions from the amino acid side chains, especially the C-terminal lysine that mimics the binding pattern observed for lisinopril. Moreover, the inhibition observed for [KGHK–Co(NH3)2]2+ contrasts with the activation of hACE by Co2+(aq), reflecting the stimulation of enzyme activity following replacement of the catalytic zinc cofactor by cobalt ion at each of the two active sites. Quantitative analysis of the dose-dependent stimulation of activity by Co2+(aq) yielded apparent affinities of 1.3 ± 0.2 and 56 ± 8 μM for the two sites in the presence of saturating Zn2+ (10 μM). Catalytic inactivation of hACE by [KGHK–Cu] + at subsaturating concentrations had previously been characterized, with k
obs = 2.9 ± 0.5 × 10−2 min−1. Under similar conditions, the same complex is found to catalytically inactivate hECE-1, with k
obs = 2.12 ± 0.16 × 10−2 min−1, demonstrating the potential for dual-action activity against two key drug targets in cardiovascular disease. Irreversible inactivation of a drug target represents a novel mechanism of drug action that complements existing classical inhibitor strategies that underlie current drug discovery efforts.Electronic Supplementary Material Supplementary material is available to authorized users in the online version of this article at . 相似文献
23.
Patil SS Kadam SR Patil SS Bastawde KB Khire JM Gokhale DV 《Letters in applied microbiology》2006,43(1):53-57
AIMS: To examine the potential of Lactobacillus delbrueckii mutant, Uc-3 to produce lactic acid and fructose from sucrose-based media. METHODS AND RESULTS: The mutant of L. delbrueckii NCIM 2365 was cultivated in shake flask containing hydrolysed cane sugar (sucrose)-based medium. The lactic acid yield and volumetric productivity with hydrolysed cane concentration up to 200 g l(-1) were in the range of 92-97% of the theoretical value and between 2.7 and 3.8 g l(-1) h(-1), respectively. The fructose fraction of the syrup produced was more than 95% when the total initial sugar concentration in the medium was higher (150-200 g l(-1)). There are no unwanted byproducts detected in the fermentation broth. CONCLUSIONS: We demonstrated that L. delbrueckii mutant Uc-3 was able to utilize glucose preferentially to produce lactic acid and fructose from hydrolysed cane sugar in batch fermentation process. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings will be useful in the production of lactic acid and high fructose syrups using media with high concentrations of sucrose-based raw materials. This approach can lead to modification of the traditional fermentation processes to obtain value-added byproducts, attaining better process economics. 相似文献
24.
Smith B Chang HH Medda F Gokhale V Dietrich J Davis A Meuillet EJ Hulme C 《Bioorganic & medicinal chemistry letters》2012,22(10):3567-3570
This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE(2) reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R(2) position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R(1)=Me, R(2)=4-OPh-Ph, R(3)=CH(OH)Me) exhibited the most potent cellular PGE(2) reducing activity of the entire series (EC(50)=90 nM) with an IC(50) value for COX-2 inhibition of >5 μM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity. 相似文献
25.
Adkar BV Tripathi A Sahoo A Bajaj K Goswami D Chakrabarti P Swarnkar MK Gokhale RS Varadarajan R 《Structure (London, England : 1993)》2012,20(2):371-381
Highlights? Individual mutant phenotypes in a saturation library derived via deep sequencing ? Residue depth and active-site residue derivation from mutant phenotypes ? Mutant-phenotype-derived parameters used for protein model discrimination ? Derivation of sequence-structure-function relationships without protein isolation 相似文献
26.
Duclos D Gokhale S Bacilieri R Ducrocq V 《Animal : an international journal of animal bioscience》2008,2(1):160-166
Milk production data from Holstein × Zebu cows in small farms (2.4 cows per farm on average) in Maharashtra, India, followed by Bharatiya Agro Industries Foundation (BAIF), an Indian non-governmental organisation, were analysed to evaluate the impact of simplified milk-recording systems. The aim was to investigate, in developing tropical areas, less-costly protocols compared with the one currently implemented at BAIF, used as a reference. The latter can be considered an 'AT2' protocol with the recording made by specialised technicians at 2-week intervals. The simplified protocols were simulated from an initial data file by sampling test days according to each protocol. Bias and accuracy on the 305-day cow milk production and on the resulting reliability of the estimated breeding value of bulls were the criteria used in the comparison with the reference protocol. One type of simplified protocol considered an increase in the interval between two tests to at least 4 and up to 8 weeks. Another alternative studied corresponded to the situation where milk yield information measured by the farmer is collected by the artificial insemination technicians themselves when visiting a farm. This could be an option in the case of very small herd sizes (two or three cows). The results suggest that simplifying the current milk-recording protocol leads to a clear decrease in accuracy of estimating 305-day cow production but it has a limited effect on the reliability of bull proofs. No economic comparison was carried out, but the results strongly suggest that properly managed simplified milk-recording schemes could permit a substantial decrease of costs of milk recording per cow without damaging the efficiency of progeny testing in tropical areas with small herd size. Moreover, with the proposed simplified milk-recording protocols, up to three to four times more bulls could be tested with the same number of records. 相似文献
27.
Ghosh R Chhabra A Phatale PA Samrat SK Sharma J Gosain A Mohanty D Saran S Gokhale RS 《The Journal of biological chemistry》2008,283(17):11348-11354
Dictyostelium discoideum exhibits the largest repository of polyketide synthase (PKS) proteins of all known genomes. However, the functional relevance of these proteins in the biology of this organism remains largely obscure. On the basis of computational, biochemical, and gene expression studies, we propose that the multifunctional Dictyostelium PKS (DiPKS) protein DiPKS1 could be involved in the biosynthesis of the differentiation regulating factor 4-methyl-5-pentylbenzene-1,3-diol (MPBD). Our cell-free reconstitution studies of a novel acyl carrier protein Type III PKS didomain from DiPKS1 revealed a crucial role of protein-protein interactions in determining the final biosynthetic product. Whereas the Type III PKS domain by itself primarily produces acyl pyrones, the presence of the interacting acyl carrier protein domain modulates the catalytic activity to produce the alkyl resorcinol scaffold of MPBD. Furthermore, we have characterized an O-methyltransferase (OMT12) from Dictyostelium with the capability to modify this resorcinol ring to synthesize a variant of MPBD. We propose that such a modification in vivo could in fact provide subtle variations in biological function and specificity. In addition, we have performed systematic computational analysis of 45 multidomain PKSs, which revealed several unique features in DiPKS proteins. Our studies provide a new perspective in understanding mechanisms by which metabolic diversity could be generated by combining existing functional scaffolds. 相似文献
28.
Trimukhe KD Mahadik ND Gokhale DV Varma AJ 《International journal of biological macromolecules》2008,43(5):422-425
Chitosan and its derivatives have been used as affinity matrices for purification of lipase from Aspergillus niger NCIM 1207. Trimellitic anhydride (TMA)-crosslinked deacetylated chitin adsorbed lipase selectively, yielding approximately 5-fold purification of the crude lipase with 70% yield. Further 9-fold purification occurred on eluting through Sephacryl-100. These results suggest that chitosan derivatives can be used as inexpensive biopolymer matrices for the purification of lipases for industrial applications. 相似文献
29.
Utilization of Molasses Sugar for Lactic Acid Production by Lactobacillus delbrueckii subsp. delbrueckii Mutant Uc-3 in Batch Fermentation 下载免费PDF全文
Arti Dumbrepatil Mukund Adsul Shivani Chaudhari Jayant Khire Digambar Gokhale 《Applied microbiology》2008,74(1):333-335
Efficient lactic acid production from cane sugar molasses by Lactobacillus delbrueckii mutant Uc-3 in batch fermentation process is demonstrated. Lactic acid fermentation using molasses was not significantly affected by yeast extract concentrations. The final lactic acid concentration increased with increases of molasses sugar concentrations up to 190 g/liter. The maximum lactic acid concentration of 166 g/liter was obtained at a molasses sugar concentration of 190 g/liter with a productivity of 4.15 g/liter/h. Such a high concentration of lactic acid with high productivity from molasses has not been reported previously, and hence mutant Uc-3 could be a potential candidate for economical production of lactic acid from molasses at a commercial scale. 相似文献
30.
Nathan D. Mathewson Orr Ashenberg Itay Tirosh Simon Gritsch Elizabeth M. Perez Sascha Marx Livnat Jerby-Arnon Rony Chanoch-Myers Toshiro Hara Alyssa R. Richman Yoshinaga Ito Jason Pyrdol Mirco Friedrich Kathrin Schumann Michael J. Poitras Prafulla C. Gokhale L. Nicolas Gonzalez Castro Marni E. Shore Kai W. Wucherpfennig 《Cell》2021,184(5):1281-1298.e26