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onsdag 1 juni 2016

Anthranilaatista tryptofaania M Tbc:n syntaasientsyymillä ...

Plastidi

pseudomonas:  fenylalaniinin, tyrosiinin ja tryptofaanin synteesitiet glukoosista  anthranilaatista)

  •  M tbc syntetisoi välttämättömän tryptofaaninsa anthranilaattitietä.
Acta Crystallogr D Biol Crystallogr. 2015 Nov;71(Pt 11):2297-308. doi: 10.1107/S1399004715017216. Epub 2015 Oct 31.
Structure and inhibition of subunit I of the anthranilate synthase complex of Mycobacterium tuberculosis and expression of the active complex.
Abstract The tryptophan-biosynthesis pathway is essential for Mycobacterium tuberculosis (Mtb) to cause disease, but not all of the enzymes that catalyse this pathway in this organism have been identified. The structure and function of the enzyme complex that catalyses the first committed step in the pathway, the anthranilate synthase (AS) complex, have been analysed. It is shown that the open reading frames Rv1609 (trpE) and Rv0013 (trpG) encode the chorismate-utilizing (AS-I) and glutamine amidotransferase (AS-II) subunits of the AS complex, respectively. Biochemical assays show that when these subunits are co-expressed a bifunctional AS complex is obtained. Crystallization trials on Mtb-AS unexpectedly gave crystals containing only AS-I, presumably owing to its selective crystallization from solutions containing a mixture of the AS complex and free AS-I. The three-dimensional structure reveals that Mtb-AS-I dimerizes via an interface that has not previously been seen in AS complexes. As is the case in other bacteria, it is demonstrated that Mtb-AS shows cooperative allosteric inhibition by tryptophan, which can be rationalized based on interactions at this interface. Comparative inhibition studies on Mtb-AS-I and related enzymes highlight the potential for single inhibitory compounds to target multiple chorismate-utilizing enzymes for TB drug discovery. KEYWORDS: Mycobacterium tuberculosis; anthranilate synthase complex; inhibitor design; tryptophan biosynthesis.
Taustatieto: Anthranilaatti on molekyyli, joka on  ihmisen ravinnon tryptofaanin aineenvaihdunnassa   B6- puuteessa  kumuloituva  sivutie ja siitä tulee substraattia antranilaattia   esim Tbc bakteerille, joka voi malla synteesillään palautaa antranilaatin takaisin omaksi välttämättömäksi tryptofaanikseen. sen takia  mielestäni TBC- potilaille  ja  tbc.tä estävänä  tekijänä on mm B6-vitamiinin normaali saanti aina, eikä vain INH:n yhteydessä, sillä mahdollisesti INH vain  mututaa  jo olevan vajeen todelliseksi puutteeksi.

Eräs tutkimus kroonisesta migreenistä 8CM)   antoi löytönä mm. antranilaatin kumuloitumista.
lieköhän tuota anthranilaattiekrtymä  B6- vaje- tilannetta tutkittu maailmassa ihmisen  tubiin sairastumisen kannalta.  Onhan  TBC  yleinen tauti maailmassa varsinkin  ravinto-olojen   heikentyessä.

Uusia TBC- lääkeideoita:

  • Int J Antimicrob Agents. 2016 May 10. pii: S0924-8579(16)30073-5. doi: 10.1016/j.ijantimicag.2016.04.007. [Epub ahead of print] Development of efflux pump inhibitors in antituberculosis therapy.
Resistance and tolerance to antituberculosis (anti-TB) drugs, especially the first-line drugs, has become a serious problem in anti-TB therapy. Efflux of antimicrobial agents via bacterial efflux pumps is one of the main reasons for drug resistance. Efflux pump inhibitors (EPIs) bind to efflux pumps to inhibit drug efflux and thus enhance the drug effect and reduce drug resistance. Studies on EPIs targeting the efflux pumps of Mycobacterium tuberculosis (Mtb) help to understand Mtb resistance and to identify the potential drug target and are of significance in guiding the development of new anti-TB drugs and optimal combinations. Currently, there are many potential EPIs under study, but none of them has been used clinically for anti-TB therapy. In this article, we will provide an overview on the current development of EPIs targeting the efflux pumps of Mtb and discuss their potential clinical applications.Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved. KEYWORDS:
CCCP; Efflux pump inhibitor; Mycobacterium tuberculosis; Reserpine; Tuberculosis; Verapamil





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