Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

Lloyd, Matthew D.; Yevglevskis, Maksims; Nathubhai, Amit; James, Tony D.; Threadgill, Michael D.; Woodman, Timothy J.

doi:10.1039/d0cs00540a

Cited by 13 publications

(10 citation statements)

References 281 publications

(895 reference statements)

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“…Among many possibilities, these include: Oxyanions with four different substituents at the respective C atom, occurring in the mechanism of lipases, esterases and proteases. − Protonated oxyanions with four different substituents at the tetrahedral C atom, formed in the multistep (retro)-aldolase reaction pathway from β-hydroxy ketones and aldehydes, but also in related enzyme catalyzed reactions that involve the formation of enamine and/or Schiff base intermediates covalently linked to catalytic lysine residues. − Oxyanions with four different substituents at the tetrahedral C atom as in racemases and epimerases. − Protonated oxyanions in which two of the four substituents at the respective tetrahedral C atom are formally identical, but are differently stabilized by supramolecular noncovalent H-bonding, as in the mechanisms of fluoroacetate dehalogenase, − a carbonic anhydrase mutant, and most epoxide hydrolases. − …”

Section: Proposed Classification Of Structurally Different Fleeting C...mentioning

confidence: 99%

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The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions

Reetz

Garcia‐Borràs

2021

J. Am. Chem. Soc.

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Decades of extensive research efforts by biochemists, organic chemists, and protein engineers have led to an understanding of the basic mechanisms of essentially all known types of enzymes, but in a formidable number of cases an essential aspect has been overlooked. The occurrence of short-lived chiral intermediates formed by symmetry-breaking of prochiral precursors in enzyme catalyzed reactions has been systematically neglected. We designate these elusive species as fleeting chiral intermediates and analyze such crucial questions as "Do such intermediates occur in homochiral form?" If so, what is the absolute configuration, and why did Nature choose that particular stereoisomeric form, even when the isolable final product may be achiral? Does the absolute configuration of a chiral product depend in any way on the absolute configuration of the fleeting chiral precursor? How does this affect the catalytic proficiency of the enzyme? If these issues continue to be unexplored, then an understanding of the mechanisms of many enzyme types remains incomplete. We have systematized the occurrence of these chiral intermediates according to their structures and enzyme types. This is followed by critical analyses of selected case studies and by final conclusions and perspectives. We hope that the fascinating concept of fleeting chiral intermediates will attract the attention of scientists, thereby opening an exciting new research field.

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Section: Proposed Classification Of Structurally Different Fleeting C...mentioning

confidence: 99%

“…Oxyanions with four different substituents at the tetrahedral C atom as in racemases and epimerases. − …”

Section: Proposed Classification Of Structurally Different Fleeting C...mentioning

confidence: 99%

The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions

Reetz

Garcia‐Borràs

2021

J. Am. Chem. Soc.

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Section: Resultsmentioning

confidence: 99%

“…Glutamate racemase is an essential enzyme for the biosynthesis of the bacterial cell wall; it was studied intensively in the last decades as a possible target for antibacterial drug discovery. 21,[43][44][45][46] The results of the inhibitory activity measurements are presented in Table 2. It might be seen that some amino acids with different substitution patterns (i.e.…”

Section: Biological Evaluationmentioning

confidence: 99%

A stereochemical journey around spirocyclic glutamic acid analogs

Chernykh

Radchenko

et al. 2022

Org. Biomol. Chem.

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“…Sources: Aebutus unedo (strawberry-tree), honey, Xanthomonas campestris pv. Phaseoll, Yarrownia lipolytica Alr-2 inhibitors found to be active against Aeromonas hydrophila IC 50 value= 0.2 µM MIC value= 1.73 µg/mL Potent inhibitor of Alr isolated from Streptococcus iniae HNM-1 18,33,34 9.…”

Section: Homogentisic Acidmentioning

confidence: 99%

Untitled

2023

IJPSR

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Enzyme Alanine racemase is well known for performing a predominating role in mycobacterium cell wall synthesis. D-alanine provided by Alanine racemase serves as a peptidoglycan precursor, utterly vital for maintaining the growth and integrity of the cell wall. The lipid-rich mycobacterium cell wall is prevalent amidst prokaryotes with immense potential of becoming a therapeutic target for new drug discovery. The imperative role of Alanine racemase in mycobacterium cell wall synthesis implies that its inhibition is of uttermost priority in order to deal with various pathogenic infections. Interference with metabolic processes, lack of specificity, and cellular toxicity caused by several known inhibitors prompted renewed efforts by researchers to discover new and improved inhibitors with better therapeutic indexes. This paper provides an overview of the updated status of reported Alanine racemase inhibitors based on shreds of evidence in literature so that more precise inhibitors could be explored, designed, and identified to rationalize the overall drug discovery process, which will be true serendipity for the mankind.

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Racemases and epimerases operating through a 1,1-proton transfer mechanism: reactivity, mechanism and inhibition

Abstract: Racemases and epimerases using a deprotonation/reprotonation mechanism are important drug targets and have important biotechnological applications. This review focuses on the reactivity, mechanism, and inhibition of these versatile enzymes.

Cited by 13 publications

References 281 publications

The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions

The Unexplored Importance of Fleeting Chiral Intermediates in Enzyme-Catalyzed Reactions

A stereochemical journey around spirocyclic glutamic acid analogs

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