Itaconate (methylenesuccinate) was recently identified as a mammalian metabolite whose production is substantially induced during macrophage activation. This compound is a potent inhibitor of isocitrate lyase, a key enzyme of the glyoxylate cycle, which is a pathway required for the survival of many pathogens inside the eukaryotic host. Here we show that numerous bacteria, notably many pathogens such as Yersinia pestis and Pseudomonas aeruginosa, have three genes for itaconate degradation. They encode itaconate coenzyme A (CoA) transferase, itaconyl-CoA hydratase and (S)-citramalyl-CoA lyase, formerly referred to as CitE-like protein. These genes are known to be crucial for survival of some pathogens in macrophages. The corresponding enzymes convert itaconate into the cellular building blocks pyruvate and acetyl-CoA, thus enabling the bacteria to metabolize itaconate and survive in macrophages. The itaconate degradation and detoxification pathways of Yersinia and Pseudomonas are the result of convergent evolution. This work revealed a common persistence factor operating in many pathogenic bacteria.
bPseudomonas aeruginosa, Yersinia pestis, and many other bacteria are able to utilize the C 5 -dicarboxylic acid itaconate (methylenesuccinate). Itaconate degradation starts with its activation to itaconyl coenzyme A (itaconyl-CoA), which is further hydrated to (S)-citramalyl-CoA, and citramalyl-CoA is finally cleaved into acetyl-CoA and pyruvate. The xenobiotic-degrading betaproteobacterium Burkholderia xenovorans possesses a P. aeruginosa-like itaconate degradation gene cluster and is able to grow on itaconate and its isomer mesaconate (methylfumarate). Although itaconate degradation proceeds in B. xenovorans in the same way as in P. aeruginosa, the pathway of mesaconate utilization is not known. Here, we show that mesaconate is metabolized through its hydration to (S)-citramalate. The latter compound is then metabolized to acetyl-CoA and pyruvate with the participation of two enzymes of the itaconate degradation pathway, a promiscuous itaconate-CoA transferase able to activate (S)-citramalate in addition to itaconate and (S)-citramalyl-CoA lyase. The first reaction of the pathway, the mesaconate hydratase (mesaconase) reaction, is catalyzed by a class I fumarase. As this enzyme (Bxe_A3136) has similar efficiencies (k cat /K m ) for both fumarate and mesaconate hydration, we conclude that B. xenovorans class I fumarase is in fact a promiscuous fumarase/ mesaconase. This promiscuity is physiologically relevant, as it allows the growth of this bacterium on mesaconate as a sole carbon and energy source. I taconate (methylenesuccinate) is an industrially important fungal product and a common carbon source for various soil bacteria (1). Still, the importance of other C 5 -dicarboxylic acids such as ethylmalonate, methylsuccinate, citramalate (␣-methylmalate), and mesaconate (methylfumarate) was neglected for decades. Yet, the participation of these compounds in several central metabolic pathways has been shown in the last 15 years. Examples are the autotrophic 3-hydroxypropionate bi-cycle as well as the anaplerotic ethylmalonyl coenzyme A (ethylmalonyl-CoA) pathway and methylaspartate cycle functioning for the assimilation of C 2 units (2-6). Furthermore, mesaconate and citramalate are intermediates of the methylaspartate pathway of glutamate fermentation functioning in many (facultative) anaerobic bacteria (7).Itaconate was recently identified as a mammalian metabolite whose production is substantially induced during macrophage activation (8, 9). As itaconate is known as a potent inhibitor of the glyoxylate cycle, a metabolic pathway important for many pathogens during infection, itaconate production by macrophages is regarded as part of the antibacterial response of macrophages (9-11). Interestingly, many pathogens contain genes involved in itaconate assimilation (11). The capability to degrade itaconate promotes the survival and infectivity of pathogens inside the hosts (10-12). Bacterial itaconate degradation involves three steps, i.e., itaconate activation to itaconyl-CoA, its hydration (via mesaconyl-CoA) to ...
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