Regioselectivity in the Homolytic Cleavage of S-Adenosylmethionine

Kampmeier, J. A.

doi:10.1021/bi101509u

Cited by 32 publications

(43 citation statements)

References 22 publications

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“…These calculations suggest that the single electron transfer involves passage from the unique iron site to the AdoMet Sδ + orbital, promoting reductive cleavage and radical generation at the C5' of AdoMet [24]. Alternatively, cleavage can be described as a radical displacement reaction, similar to that observed at sulfoxide centers [73].…”

Section: Dft Calculations Based On High Resolution Structures Of Hydementioning

confidence: 77%

Structural diversity in the AdoMet radical enzyme superfamily

Dowling

Vey²,

Croft³

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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AdoMet radical enzymes are involved in processes such as cofactor biosynthesis, anaerobic metabolism, and natural product biosynthesis. These enzymes utilize the reductive cleavage of Sadenosylmethionine (AdoMet) to afford L-methionine and a transient 5'-deoxyadenosyl radical, which subsequently generates a substrate radical species. By harnessing radical reactivity, the AdoMet radical enzyme superfamily is responsible for an incredible diversity of chemical transformations. Structural analysis reveals that family members adopt a full or partial Triosephosphate Isomerase Mutase (TIM) barrel protein fold, containing core motifs responsible for binding a catalytic [4Fe-4S] cluster and AdoMet. Here we evaluate over twenty structures of AdoMet radical enzymes and classify them into two categories: traditional and ThiC-like (named for the structure of 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate synthase (ThiC)). In light of new structural data, we reexamine the traditional structural motifs responsible for binding the [4Fe-4S] cluster and AdoMet, and compare and contrast these motifs with the ThiC case. We also review how structural data combine with biochemical, spectroscopic, and computational data to help us understand key features of this enzyme superfamily, such as the energetics, the triggering, and the molecular mechanisms of AdoMet reductive cleavage.

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Section: Dft Calculations Based On High Resolution Structures Of Hydementioning

confidence: 77%

Structural diversity in the AdoMet radical enzyme superfamily

Dowling

Vey²,

Croft³

et al. 2012

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…This analysis would suggest that the S–C bond that is oriented trans to the sulfonium S–cluster interaction, and thus the S–C bond whose antibonding orbital has a lobe positioned to accept an electron from the Fe–S cluster, is the bond that will undergo homolytic cleavage. 33 Consistent with this idea, most structurally characterized radical SAM enzymes appear to bind SAM such that the S–C(5′) bond is in the trans position. 34 Because there are currently no structures available in the SAM-bound state S–C(γ) bond-cleaving enzymes, it remains to be determined whether these enzymes will exhibit an alternate configuration of SAM relative to the cluster.…”

Section: Unifying Structural and Mechanistic Features Of The Radical mentioning

confidence: 88%

RadicalS-Adenosylmethionine Enzymes

et al. 2014

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“…Dph2, termed a radical SAM-like enzyme because it lacks the sequence and structural characteristics of the superfamily (including the CX 3 CX 2 C the TIM barrel fold) but still utilizes a [4Fe–4S] cluster to carry out SAM radical chemistry, also cleaves the S—C(γ) bond of SAM to produce MTA and the proposed ACP radical [6,7]. How radical SAM enzymes control the regioselectivity of SAM cleavage is unclear but the orientation of SAM with respect to the [4Fe–4S] cluster likely plays a role [7,57]. In addition to the radical SAM cysteine binding motif, Gdh-AE contains two additional cysteine-rich domains, CX 2 CX 2 -CX 3 C, which are ferredoxin-like [4Fe–4S] cluster binding domains [8,29].…”

Section: The Glycyl Radical Enzymes: Substrates For the Gre–aesmentioning

confidence: 99%

Glycyl radical activating enzymes: Structure, mechanism, and substrate interactions

Shisler

Broderick

2014

Archives of Biochemistry and Biophysics

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The glycyl radical enzyme activating enzymes (GRE–AEs) are a group of enzymes that belong to the radical S-adenosylmethionine (SAM) superfamily and utilize a [4Fe–4S] cluster and SAM to catalyze H-atom abstraction from their substrate proteins. GRE–AEs activate homodimeric proteins known as glycyl radical enzymes (GREs) through the production of a glycyl radical. After activation, these GREs catalyze diverse reactions through the production of their own substrate radicals. The GRE–AE pyruvate formate lyase activating enzyme (PFL-AE) is extensively characterized and has provided insights into the active site structure of radical SAM enzymes including GRE–AEs, illustrating the nature of the interactions with their corresponding substrate GREs and external electron donors. This review will highlight research on PFL-AE and will also discuss a few GREs and their respective activating enzymes.

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Regioselectivity in the Homolytic Cleavage of S-Adenosylmethionine

Cited by 32 publications

References 22 publications

Structural diversity in the AdoMet radical enzyme superfamily

Structural diversity in the AdoMet radical enzyme superfamily

RadicalS-Adenosylmethionine Enzymes

Glycyl radical activating enzymes: Structure, mechanism, and substrate interactions

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