03086nas a2200457   4500008004100000022001400041245010700055210006900162260000800231300001600239490000800255520166200263653001701925653002501942653001701967653000901984100002301993700001902016700001902035700002402054700002102078700002602099700001802125700002802143700001702171700003002188700001802218700001802236700002202254700001802276700001902294700002702313700002002340700003002360700002202390700002102412700002502433700002402458700002402482856012202506       2022                        eng d  a0027-842400aKupyaphores are zinc homeostatic metallophores required for colonization of Mycobacterium tuberculosis0 aKupyaphores are zinc homeostatic metallophores required for colo  cFEB  ae21102931190 v1193 a<p>
	Mycobacterium tuberculosis (Mtb) endures a combination of metal scarcity and toxicity throughout the human infection cycle, contributing to complex clinical manifestations. Pathogens counteract this paradoxical dysmetallostasis by producing specialized metal trafficking systems. Capture of extracellular metal by siderophores is a widely accepted mode of iron acquisition, and Mtb iron-chelating siderophores, mycobactin, have been known since 1965. Currently, it is not known whether Mtb produces zinc scavenging molecules. Here, we characterize low-molecular-weight zinc-binding compounds secreted and imported by Mtb for zinc acquisition. These molecules, termed kupyaphores, are produced by a 10.8 kbp biosynthetic cluster and consists of a dipeptide core of ornithine and phenylalaninol, where amino groups are acylated with isonitrilecontaining fatty acyl chains. Kupyaphores are stringently regulated and support Mtb survival under both nutritional deprivation and intoxication conditions. A kupyaphore-deficient Mtb strain is unable to mobilize sufficient zinc and shows reduced fitness upon infection. We observed early induction of kupyaphores in Mtb-infected mice lungs after infection, and these metabolites disappeared after 2 wk. Furthermore, we identify an Mtb-encoded isonitrile hydratase, which can possibly mediate intracellular zinc release through covalent modification of the isonitrile group of kupyaphores. Mtb clinical strains also produce kupyaphores during early passages. Our study thus uncovers a previously unknown zinc acquisition strategy of Mtb that could modulate host-pathogen interactions and disease outcome.</p>
10ametallophore10anutritional immunity10atuberculosis10azinc1 aMehdiratta, Kritee1 aSingh, Shubham1 aSharma, Sachin1 aBhosale, Rashmi, S.1 aChoudhury, Rahul1 aMasal, Dattatraya, P.1 aManocha, Alzu1 aDhamale, Bhushan, Dilip1 aKhan, Naseem1 aAsokachandran, Vivekanand1 aSharma, Pooja1 aIkeh, Melanie1 aBrown, Amanda, C.1 aParish, Tanya1 aOjha, Anil, K.1 aMichael, Joy, Sarojini1 aFaruq, Mohammed1 aMedigeshi, Guruprasad, R.1 aMohanty, Debasisa1 aReddy, Srinivasa1 aNatarajan, Vivek, T.1 aKamat, Siddhesh, S.1 aGokhale, Rajesh, S.  uhttps://library.ncl.res.in/content/kupyaphores-are-zinc-homeostatic-metallophores-required-colonization-mycobacterium02635nas a2200265   4500008004100000022001400041245012400055210006900179260000900248300001400257490000700271520171400278100002401992700002302016700002002039700002602059700002102085700002302106700002102129700002602150700002402176700002202200700002402222856012302246       2025                        eng d  a1554-892900aEnzymatic pathway for kupyaphore degradation in mycobacterium tuberculosis: mechanism of metal homeostasis and turnover0 aEnzymatic pathway for kupyaphore degradation in mycobacterium tu  cJUN   a1492-15040 v203 a<p>
	Metallophores are essential for metal homeostasis, regulating availability, and mediating host-pathogen interactions. Kupyaphores are specialized metallophores produced by Mycobacterium tuberculosis (Mtb) that primarily chelate zinc to support bacterial survival. Elevated kupyaphore levels early in infection highlight their importance, while their rapid decline, despite increasing bacterial loads, indicates tightly regulated mechanisms of production, consumption, and degradation. However, the processes driving kupyaphore catabolism and their role in preventing zinc toxicity in Mtb remain unclear. Here, we show that covalent modification of the isonitrile moiety in kupyaphores releases zinc, triggering degradation through a sequential three-step enzymatic pathway encoded by Mtb. Isonitrile hydratase converts isonitrile groups into formamides, which are subsequently processed into amines by N-substituted formamide deformylase and ultimately oxidized to beta-ketoesters by amine oxidases. The biological significance of this pathway is underscored by the upregulation of these genes under metal-depleted and biofilm-forming conditions. Mutant Mtb strains lacking these genes exhibit impaired growth in metal-limiting environments and reduced levels of biofilm formation. Catalytic intermediates detected in Mtb cultures and infected mouse lung tissues confirm the pathway's in vivo activity. Further, genome mining reveals that similar enzymes are conserved across organisms producing isonitrile-containing metabolites, emphasizing the broader importance of this pathway. Understanding these processes could pave the way for novel therapeutic strategies targeting kupyaphore catabolism.</p>
1 aBhosale, Rashmi, S.1 aChakraborty, Arnab1 aWong, Tsung-Yun1 aMasal, Dattatraya, P.1 aChoudhury, Rahul1 aSrivastava, Sonali1 aReddy, Srinivasa1 aAldrich, Courtney, C.1 aKamat, Siddhesh, S.1 aMohanty, Debasisa1 aGokhale, Rajesh, S.  uhttps://library.ncl.res.in/content/enzymatic-pathway-kupyaphore-degradation-mycobacterium-tuberculosis-mechanism-metal