Mechanism of Rate Acceleration of Radical C–C Bond Formation Reaction by a Radical SAM GTP 3′,8-Cyclase

Pang, Haoran; Lilla, Edward A.; Zhang, Pan; Zhang, Du; Shields, Thomas P.; Scott, Lincoln G.; Yang, Weitao; Yokoyama, Kenichi

doi:10.1021/jacs.0c01200

Cited by 18 publications

(44 citation statements)

References 88 publications

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“…Initially, cyclization of GTP via carbon rearrangement, catalyzed by MoaA and MoaC, leads to the formation of a cyclic pyranopterin monophosphate (cPMP) (Wuebbens et al, 2000;Hanzelmann and Schindelin, 2004;Hover et al, 2013Hover et al, , 2015Srivastava et al, 2013;Yokoyama and Lilla, 2018;Pang et al, 2020). Sulfuration of cPMP, the second step, is carried out by PPT synthase, a heterotetrametric (α 2 β 2 ) complex consisting of the MoaD and MoaE proteins, and leads to the formation of a PPT molecule (Pitterle et al, 1993;Daniels et al, 2008) (Figure 2).…”

Section: The Molybdenum-pyranopterin Cofactor and Its Biosynthesismentioning

confidence: 99%

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

2020

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Mononuclear molybdoenzymes are highly versatile catalysts that occur in organisms in all domains of life, where they mediate essential cellular functions such as energy generation and detoxification reactions. Molybdoenzymes are particularly abundant in bacteria, where over 50 distinct types of enzymes have been identified to date. In bacterial pathogens, all aspects of molybdoenzyme biology such as molybdate uptake, cofactor biosynthesis, and function of the enzymes themselves, have been shown to affect fitness in the host as well as virulence. Although current studies are mostly focused on a few key pathogens such as Escherichia coli, Salmonella enterica, Campylobacter jejuni, and Mycobacterium tuberculosis, some common themes for the function and adaptation of the molybdoenzymes to pathogen environmental niches are emerging. Firstly, for many of these enzymes, their role is in supporting bacterial energy generation; and the corresponding pathogen fitness and virulence defects appear to arise from a suboptimally poised metabolic network. Secondly, all substrates converted by virulence-relevant bacterial Mo enzymes belong to classes known to be generated in the host either during inflammation or as part of the host signaling network, with some enzyme groups showing adaptation to the increased conversion of such substrates. Lastly, a specific adaptation to bacterial in-host survival is an emerging link between the regulation of molybdoenzyme expression in bacterial pathogens and the presence of immune system-generated reactive oxygen species. The prevalence of molybdoenzymes in key bacterial pathogens including ESKAPE pathogens, paired with the mounting evidence of their central roles in bacterial fitness during infection, suggest that they could be important future drug targets.

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Section: The Molybdenum-pyranopterin Cofactor and Its Biosynthesismentioning

confidence: 99%

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

2020

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“…Enforcement of a nominally unfavorable substrate conformation to overcome otherwise high activation barriers was also discovered in the rSAM enzyme MoaA, which cyclizes guanosine triphosphate (GTP) to generate 3′,8-cyclo-7,8-dihydro-GTP (3′,8-cH 2 GTP) during biosynthesis of the essential molybdenum cofactor, Moco ( Figure 5 A) [ 44 ]. DFT-based analyses reveal that constraining both the nucleobase and triphosphate moiety, consistent with observed hydrogen bonding interactions between active site constituents, facilitates deformation of the substrate ( Table 1 ) [ 45 ]. The resultant molecular arrangement decreases the activation energy of cyclization.…”

Section: Density Functional Theorymentioning

confidence: 60%

Computational Approaches: An Underutilized Tool in the Quest to Elucidate Radical SAM Dynamics

Davis¹

2021

Molecules

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Enzymes are biological catalysts whose dynamics enable their reactivity. Visualizing conformational changes, in particular, is technically challenging, and little is known about these crucial atomic motions. This is especially problematic for understanding the functional diversity associated with the radical S-adenosyl-L-methionine (SAM) superfamily whose members share a common radical mechanism but ultimately catalyze a broad range of challenging reactions. Computational chemistry approaches provide a readily accessible alternative to exploring the time-resolved behavior of these enzymes that is not limited by experimental logistics. Here, we review the application of molecular docking, molecular dynamics, and density functional theory, as well as hybrid quantum mechanics/molecular mechanics methods to the study of these enzymes, with a focus on understanding the mechanistic dynamics associated with turnover.

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“…The electronic structure and bonding feature of the [4Fe-4S] cluster has been extensively studied before. [13] Sulfides and thiolates in [4Fe-4S] cluster are weak field ligands,resulting in asmall ligand field splitting.However,the first-row transition metal Fe possesses ar elatively large exchange interaction within its d-orbitals. [12,14] Such exchange stabilizations would prefer the high-spin state on each individual Fe in [4Fe-4S] cluster.M eanwhile,t he Heisenberg exchange coupling effects,w hich represent aw eak covalent bonding between Sbridged Fe-Fep airs,w ould favor the antiferromagnetic coupling between the Fe-Fep airs.…”

Section: Resultsmentioning

confidence: 99%

Spin‐Regulated Electron Transfer and Exchange‐Enhanced Reactivity in Fe₄S₄‐Mediated Redox Reaction of the Dph2 Enzyme During the Biosynthesis of Diphthamide

2021

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The [4Fe-4S]-dependent radical S-adenosylmethionine (SAM) proteins is one of large families of redox enzymes that are able to carry apanoply of challenging transformations. Despite the extensive studies of structure-function relationships of radical SAM (RS) enzymes,t he electronic statedependent reactivity of the [4Fe-4S] cluster in these enzymes remains elusive.U sing combined MD simulations and QM/ MM calculations,wedeciphered the electronic state-dependent reactivity of the [4Fe-4S] cluster in Dph2, ak ey enzyme involved in the biosynthesis of diphthamide.O ur calculations show that the reductive cleavage of the S À C (g) bond is highly dependent on the electronic structure of [4Fe-4S].Interestingly, the six electronic states can be classified into alow-energy and ahigh-energy groups,whichare correlated with the net spin of Fe4atom ligated to SAM. Due to the driving force of Fe4ÀC (g) bonding,the net spin on the Fe4moiety dictate the shift of the opposite spin electron from the Fe1-Fe2-Fe3 blockt oS AM. Such spin-regulated electron transfer results in the exchangeenhanced reactivity in the lower-energy group compared with those in the higher-energy group.T his reactivity principle provides fundamental mechanistic insights into reactivities of [4Fe-4S] cluster in RS enzymes.

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Mechanism of Rate Acceleration of Radical C–C Bond Formation Reaction by a Radical SAM GTP 3′,8-Cyclase

Abstract: While the number of characterized radical S-adenosyl-L-methionine (SAM) enzymes is *

Cited by 18 publications

References 88 publications

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

Computational Approaches: An Underutilized Tool in the Quest to Elucidate Radical SAM Dynamics

Spin‐Regulated Electron Transfer and Exchange‐Enhanced Reactivity in Fe₄S₄‐Mediated Redox Reaction of the Dph2 Enzyme During the Biosynthesis of Diphthamide

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Mechanism of Rate Acceleration of Radical C–C Bond Formation Reaction by a Radical SAM GTP 3′,8-Cyclase

Abstract: While the number of characterized radical S-adenosyl-L-methionine (SAM) enzymes is *

Cited by 18 publications

References 88 publications

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

Molybdenum Enzymes and How They Support Virulence in Pathogenic Bacteria

Computational Approaches: An Underutilized Tool in the Quest to Elucidate Radical SAM Dynamics

Spin‐Regulated Electron Transfer and Exchange‐Enhanced Reactivity in Fe4S4‐Mediated Redox Reaction of the Dph2 Enzyme During the Biosynthesis of Diphthamide

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Spin‐Regulated Electron Transfer and Exchange‐Enhanced Reactivity in Fe₄S₄‐Mediated Redox Reaction of the Dph2 Enzyme During the Biosynthesis of Diphthamide