METALLOCHAPERONES: The partitioning of metals to delivery pathways

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A large proportion of the reactions of life are catalysed by metals. Yet most of the enzymes driving these reactions prefer to associate with metals that prevent their activity rather than with the correct metals. Cells must therefore help enzymes to acquire the correct metals. Many metal-catalysed reactions are of high value to biotechnology and/or are the targets of antimicrobial treatments (immune systems have evolved to exploit metals to control microbes in so-called nutritional immunity, while metal-chelants and metal-ionophores have empirically been used as antimicrobials widely across the bioeconomy). For these reasons we have worked with Industry (Lonza, Syngenta, Procter and Gamble) via recent and/or on-going collaborative projects, plus with more than 480 members (about a third from outside academia) of our BBSRC Metals in Biology Network in Industrial Biotechnology and Bioenergy.Our overarching goal has always been to understand the cellular logic for metals: That is, how do cells enable proteins to acquire the correct metals? Central to this understanding is an observation that the cytosol buffers metals in an order of concentrations which is the inverse of metal-binding preferences: Thus tight-binding metals such as copper, zinc and nickel are buffered to low concentrations while weak-binding metals like magnesium, manganese and ferrous-iron, are buffered to higher concentrations. Metal-sensors are tuned to these concentrations to prevent the buffers from becoming depleted or saturated (Nature Chemical Biology, currently embargoed and in press). However this, in turn, raises an inevitable next question as to how the metal-sensor proteins themselves, along with other proteins of metal homeostasis, select the correct metals.Recently we have been able to answer the question of metal-specificity of metal-sensors by comparing properties within a set of sensors from a common cell (Salmonella). In short, the correct sensor for each metal is simply whichever one is the most sensitive in the set for that particular metal. From these recent studies we now know what factors determine the most sensitive sensor in the set. We also now know how to calculate the metal concentration that triggers each Salmonella metal sensor, and thus have unique insight into the buffered concentrations of each metal in a common cytosol. It is hypothesised that, akin to the metal-sensors, other proteins of metal-homeostasis are also tuned to these same metal concentrations. This study will now seize the opportunity to apply similar approaches to understand how a set of metal-delivery proteins select the correct metals. About one third of metalloenzymes are at the end of specialised metal delivery pathways. This solves the challenge of metal-selectivity for these metalloenzymes provided the correct metals partition onto the delivery pathways in the first place (otherwise the delivery-pathways will propagate mismetalation, and indeed there is evidence that such aberrations can occur). By making similar measurements of the metal-affinities and abundances of metal delivery proteins, it will now become possible to identify (1) which delivery protein is the best in the set for each metal and (2) which delivery proteins have affinities above or below the inferred buffered concentrations for each metal, as estimated from the metal-concentrations which trigger the metal-sensors. These data will reveal which pathways may be vulnerable to mismetalation and hence inform upon how to generate formulations which subvert the metal-handling systems (for use as antimicrobials). These data will also inform on how to enhance enzyme metalation via these pathways in support of synthetic biological approaches to biotechnology.