Control of radical chemistry in the AdoMet radical enzymes - PubMed (original) (raw)

Review

Control of radical chemistry in the AdoMet radical enzymes

Kaitlin S Duschene et al. Curr Opin Chem Biol. 2009 Feb.

Abstract

The radical AdoMet superfamily comprises a diverse set of >2800 enzymes that utilize iron-sulfur clusters and S-adenosylmethionine (SAM or AdoMet) to initiate a diverse set of radical-mediated reactions. The intricate control these enzymes exercise over the radical transformations they catalyze is an amazing feat of elegance and sophistication in biochemistry. This review focuses on the accumulating evidence for how these enzymes control this remarkable chemistry, including controlling the reactivity between the iron-sulfur cluster and AdoMet, and controlling the subsequent radical transformations.

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Figures

Figure 1

Figure 1

Representative reactions catalyzed by the radical-AdoMet enzymes. Abbreviations used: GRE-AE, glycyl radical activating enzymes such as pyruvate formate-lyase activating enzyme; LAM, lysine 2,3-aminomutase; BioB, biotin synthase; LipA, lipoyl synthase; MoaA, molybdopterin cofactor biosynthesis enzyme; HemN, oxygen-independent coproporphyrinogen oxidase; SPL, spore photoproduct lyase; MiaB, tRNA methylthiolation enzyme; ThiC and ThiH, enzymes involved in thiamine biosynthesis, TYW1, tRNA modification enzyme; AtsB, formylglycine-generating enzyme.

Figure 2

Figure 2

Common mechanistic steps proposed to be involved in the radical AdoMet enzymes.

Figure 3

Figure 3

Binding energetics and redox potentials in the radical AdoMet enzyme lysine 2,3-aminomutase. The blue scale indicates the changes in redox potential for the [4Fe-4S]2+/+ couple for the cluster in the free enzyme, for the cluster with the AdoMet bound, and for the cluster with AdoMet and lysine bound. The red scale indicates the redox potential for trialkylsulfoniums such as AdoMet (at -1800 mV) and for AdoMet bound to LAM and substrate (at -900 mV). The binding of AdoMet and substrate to the active site reduces the redox potential gap to ~300 mV.

Figure 4

Figure 4

Views of the X-ray crystal structures of lysine 2,3-aminomutase (LAM, left, minus its C-terminus), MoaA (center), and pyruvate formate-lyase activating enzyme (PFL-AE, right), each with both AdoMet and substrate bound. Note the location of the radical-AdoMet cluster at one end of the TIM barrel, with AdoMet and substrate effectively sealing off the active site. Note also that as the substrate size increases from left to right, the size of the lateral opening in the TIM barrel also increases.

Figure 5

Figure 5

Views of the X-ray crystal structures of biotin synthase (BioB, left) and HydE (right), with the lid loop highlighted in orange.

Figure 6

Figure 6

Illustration of the results of ENDOR spectroscopic studies utilizing stabilized substrate and product radical analog intermediates. In all cases, van der Waals contacts are maintained between the 5'-methyl of 5'-deoxyadenosine (dAdo) and the substrate/product radicals. Illustrations are for the substrate radicals generated upon reaction with _trans_-4,5-dehydro-L-lysine (DHLys, left), 4-thia-L-lysine (SLys, center), and the product radical generated upon equilibration of the reduced state of the enzyme with AdoMet and L-α-lysine (right).

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References

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