“Borrelidin”的意思、由来-开放百科全书

The core structure of borrelidin is biosynthesized by type I polyketide synthase (PKS), followed by post-PKS modifications. Six genes (borA1 to borA6) encode the type I PKS, composed of a loading domain and six extending modules, rather than the expected eight.^[7] Each extension module consists of the ketosynthase (KS) condensing an extender unit, either malonyl-CoA or methylmalonyl-CoA, that is loaded by the acyl transferase (AT) onto the growing polyketide, which can then be modified by further enzymes. Tailoring enzymes of type I PKS that can be involved in each module are ketoreductase (KR), dehydratase (DH), and enoyl reductase (ER). Once polyketide has gone through all of the chain extensions, it can then be released via cyclization by the thioesterase (TE).

Starting with a cyclopentane carboxylic acid starter unit that is loaded onto the acyl carrier protein, ACP, in BorA1, the polyketide intermediate, tethered to ACP via a thioester linkage, undergoes a series of extension modules.^[7] BorA2 has one extension module that loads malonyl-CoA and has a ketoreductase to reduce the β-carbonyl to a hydroxyl group.^[7] Next, BorA3, consisting of modules 2 and 3, which load malonyl-CoA and methylmalonyl-CoA, respectively, have both ketoreductase and dehydratase enzymes.^[7] BorA4 only has one extension module, loading methylmalonyl-CoA and having a ketoreductase as a tailoring enzyme.^[7] The next three chain extensions are catalyzed by BorA5, which is done through three iterative rounds of elongation and condensations with methylmalonyl-CoA from where the polyketide intermediates undergo modifications by KR, DH, and ER.^[7]^,^[8] Lastly, BorA6 loads malonyl-CoA, modifies the polyketide intermediate via a ketoreductase enzyme, and terminates the PKS cycle by a thioesterase, which releases the polyketide to form pre-Borrelidin.^[7]

The formation of the nitrile moiety of borrelidin is done by post-PKS modifications from gene products of BorI, BorJ, and BorK.^[9] The BorI gene product, a cytochrome 450 hydroxylase catalyzes the oxidation of the C12 methyl group into an allylic alcohol, which can undergo further oxidation by the gene products of BorI or BorK, an oxidoreductase, to form the formyl intermediate.^[9] The BorJ gene product, a PMP-dependent transaminase, then introduces an amine into the polyketide, generating intermediate Borrelidin B.^[7] BorI then catalyzes the conversion of the amine to an N,N-dihydroxy species and the dehydration to form borrelidin via an aldoxime intermediate.^[9]

References

1. ^{{cite journal | vauthors = Berger J, Jampolsky LM, Goldberg MW | title = Borrelidin, a new antibiotic with antiborrelia activity and penicillin enhancement properties | journal = Archives of Biochemistry | volume = 22 | issue = 3 | pages = 476–8 | date = July 1949 | pmid = 18134558 }}
2. ^{{cite journal | vauthors = Hütter R, Poralla K, Zachau HG, Zähner H | title = [Metabolic products of microorganisms. 5l. On the mechanism of action of borrelidin-inhibition of the threonine incorporation in sRNA] | journal = Biochemische Zeitschrift | volume = 344 | issue = 2 | pages = 190–6 | date = March 1966 | pmid = 4860826 }}
3. ^{{cite journal | vauthors = Paetz W, Nass G | title = Biochemical and immunological characterization of threonyl-tRNA synthetase of two borrelidin-resistant mutants of Escherichia coli K12 | journal = European Journal of Biochemistry | volume = 35 | issue = 2 | pages = 331–7 | date = June 1973 | pmid = 4577856 }}
4. ^{{cite journal | vauthors = Wakabayashi T, Kageyama R, Naruse N, Tsukahara N, Funahashi Y, Kitoh K, Watanabe Y | title = Borrelidin is an angiogenesis inhibitor; disruption of angiogenic capillary vessels in a rat aorta matrix culture model | journal = The Journal of Antibiotics | volume = 50 | issue = 8 | pages = 671–6 | date = August 1997 | pmid = 9315080 }}
5. ^{{cite journal | vauthors = Habibi D, Ogloff N, Jalili RB, Yost A, Weng AP, Ghahary A, Ong CJ | title = Borrelidin, a small molecule nitrile-containing macrolide inhibitor of threonyl-tRNA synthetase, is a potent inducer of apoptosis in acute lymphoblastic leukemia | journal = Investigational New Drugs | volume = 30 | issue = 4 | pages = 1361–70 | date = August 2012 | pmid = 21678129 | doi = 10.1007/s10637-011-9700-y }}
6. ^{{cite journal | vauthors = Azcárate IG, Marín-García P, Camacho N, Pérez-Benavente S, Puyet A, Diez A, Ribas de Pouplana L, Bautista JM | title = Insights into the preclinical treatment of blood-stage malaria by the antibiotic borrelidin | journal = British Journal of Pharmacology | volume = 169 | issue = 3 | pages = 645–58 | date = June 2013 | pmid = 23488671 | pmc = 3682711 | doi = 10.1111/bph.12156 }}
7. ^¹²³⁴⁵⁶⁷{{cite journal | vauthors = Olano C, Wilkinson B, Sánchez C, Moss SJ, Sheridan R, Math V, Weston AJ, Braña AF, Martin CJ, Oliynyk M, Méndez C, Leadlay PF, Salas JA | title = Biosynthesis of the angiogenesis inhibitor borrelidin by Streptomyces parvulus Tü4055: cluster analysis and assignment of functions | journal = Chemistry & Biology | volume = 11 | issue = 1 | pages = 87–97 | date = January 2004 | pmid = 15112998 | doi = 10.1016/j.chembiol.2003.12.018 }}
8. ^{{cite journal | vauthors = Moss SJ, Martin CJ, Wilkinson B | title = Loss of co-linearity by modular polyketide synthases: a mechanism for the evolution of chemical diversity | journal = Natural Product Reports | volume = 21 | issue = 5 | pages = 575–93 | date = October 2004 | pmid = 15459756 | doi = 10.1039/b315020h }}
9. ^¹²{{cite journal | vauthors = Olano C, Moss SJ, Braña AF, Sheridan RM, Math V, Weston AJ, Méndez C, Leadlay PF, Wilkinson B, Salas JA | title = Biosynthesis of the angiogenesis inhibitor borrelidin by Streptomyces parvulus Tü4055: insights into nitrile formation | journal = Molecular Microbiology | volume = 52 | issue = 6 | pages = 1745–56 | date = June 2004 | pmid = 15186422 | doi = 10.1111/j.1365-2958.2004.04090.x }}