Keto–Enol Tautomerism in Enzymatic Reactions

Whitman, Christian P.

doi:10.1016/b978-0-08-091283-7.00132-6

Cited by 9 publications

(10 citation statements)

References 85 publications

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“…First, the electron donating properties of the 2-hydroxy group (in 20 ) could attenuate the electrophilicity of the aldehyde carbonyl group and preclude a spontaneous ring closure (to 21 ) or make spontaneous ring closure a slow process (44). Second, dienols (such as 20 or 21 ) are likely in equilibrium with their 1,3- and 1,5-keto-enol tautomers ( 23 and 24 , Scheme 6) (45). Hydrolytic cleavage (by TomK) most reasonably occurs via the 1,3 tautomer (i.e., 23 ), yet the reaction with 4 suggests that 24 might be favored.…”

Section: Discussionmentioning

confidence: 99%

“…TomN could then tautomerize 20 (which has the 2-hydroxymuconate framework) to 25 or 26 . Although protonation can occur at C-3 (to yield 25 ) or C-5 (to yield 26 ), steric hindrance at C-5 (the aldehyde and amino acid moieties) might preclude C-5 protonation and favor formation of 25 (45). Moreover, TomN could favor one tautomer (i.e., 25 ) so that a wasteful non-enzymatic partitioning of the reactive 20 to both isomers is minimized.…”

Section: Discussionmentioning

confidence: 99%

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Kinetic, Crystallographic, and Mechanistic Characterization of TomN: Elucidation of a Function for a 4-Oxalocrotonate Tautomerase Homologue in the Tomaymycin Biosynthetic Pathway

Burks¹,

Yan²,

Johnson³

et al. 2011

Biochemistry

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The biosynthesis of the C ring of the anti-tumor antibiotic agent, tomaymycin, is proposed to proceed through five enzyme-catalyzed steps from L-tyrosine. The genes encoding these enzymes have recently been cloned and their functions tentatively assigned, but there is limited biochemical evidence supporting the assignments of the last three steps. One enzyme, TomN, shows 58% pairwise sequence similarity with 4-oxalocrotonate tautomerase (4-OT), an enzyme found in a catabolic pathway for aromatic hydrocarbons. The TomN sequence includes three amino acids (Pro-1, Arg-11, and Arg-39) that have been identified as critical catalytic residues in 4-OT. However, the proposed substrate for TomN is very different from the one processed by 4-OT. In order to establish the function and mechanism of TomN and its relationship to 4-OT, kinetic, mutagenic, and structural studies have been carried out. The kinetic parameters for TomN, and four alanine mutants, P1A, R11A, R39A, and R61A, were determined using 2-hydroxymuconate, the substrate for 4-OT. The TomN-catalyzed reaction using this substrate compares favorably to that of 4-OT. In addition, the kinetic parameters for the P1A, R11A, and R39A mutant of TomN parallel the trends observed for the corresponding 4-OT mutants, implicating an analogous mechanism. A high resolution crystal structure (1.4 Å) of TomN shows that the overall structure and the active site region are highly similar to those of 4-OT with an RMS deviation of 0.81 Å. Moreover, key active site residues are positionally conserved. The combined results suggest that the tentative assignment for TomN and the proposed sequence of events in the biosynthetic pathway leading to the formation of the C ring of tomaymycin might not be correct. An alternative pathway that awaits biochemical confirmation is proposed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Kinetic, Crystallographic, and Mechanistic Characterization of TomN: Elucidation of a Function for a 4-Oxalocrotonate Tautomerase Homologue in the Tomaymycin Biosynthetic Pathway

Burks¹,

Yan²,

Johnson³

et al. 2011

Biochemistry

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“…1) [2]. Thus far, the superfamily consists of five families represented by 4-OT [1], 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI) [4, 5], macrophage migration inhibitory factor (MIF) [6–9], cis -3-chloroacrylic acid dehalogenase ( cis -CaaD) [10], and malonate semialdehyde decarboxylase (MSAD) [11]. The 4-OT family includes trans- 3-chloroacrylic acid dehalogenase (CaaD) [3, 12].…”

Section: Introductionmentioning

confidence: 99%

“…Recent stereochemical findings suggest that 4-OT more likely catalyzes a simple 1,5-keto-enol tautomerization of 2 to 3 where Pro-1 functions as a general base and abstracts the 2-hydroxyl proton and delivers it stereoselectively to the C-5 position [19, 24]. CHMI, a trimer where each monomer is made up of 125 amino acids, functions similarly to 4-OT but uses 5-(carboxymethyl)-2-hydroxymuconate as its substrate [5, 19, 21]. The structural and biological properties of CHMI have been previously reviewed [5].…”

Section: Introductionmentioning

confidence: 99%

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The chemical versatility of the β–α–β fold: Catalytic promiscuity and divergent evolution in the tautomerase superfamily

Poelarends

Veetil

Whitman

2008

Cell. Mol. Life Sci.

163

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Tautomerase superfamily members have an amino-terminal proline and a β–α–β fold, and include 4-oxalocrotonate tautomerase (4-OT), 5-(carboxymethyl)-2-hydroxymuconate isomerase (CHMI), trans- and cis-3-chloroacrylic acid dehalogenase (CaaD and cis-CaaD, respectively), malonate semialdehyde decarboxylase (MSAD), and macrophage migration inhibitory factor (MIF), which exhibits a phenylpyruvate tautomerase (PPT) activity. Pro-1 is a base (4-OT, CHMI, the PPT activity of MIF) or an acid (CaaD, cis-CaaD, MSAD). Components of the catalytic machinery have been identified and mechanistic hypotheses formulated. Characterization of new homologues shows that these mechanisms are incomplete. 4-OT, CaaD, cis-CaaD, and MSAD also have promiscuous activities with a hydratase activity in CaaD, cis-CaaD, and MSAD, PPT activity in CaaD and cis-CaaD, and CaaD and cis-CaaD activities in 4-OT. The shared promiscuous activities provide evidence for divergent evolution from a common ancestor, give hints about mechanistic relationships, and implicate catalytic promiscuity in the emergence of new enzymes.

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Encapsulation of AGE‐Breaker Alagebrium by Cucurbit[7]uril Improved the Stability of Both Its Carbonyl α‐Hydrogen and Thiazolium C2‐Hydrogen

Ding

Yin

et al. 2016

Chemistry An Asian Journal

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As determined by both H NMR and UV/Vis spectroscopic titration, ESI-MS, isothermal titration calorimetry, and DFT molecular modeling, advanced glycation end products (AGE) breaker alagebrium (ALA) formed 1:1 guest-host inclusion complexes with cucurbit[7]uril (CB[7]), with a binding affinity, K , in the order of magnitude of 10 m , thermodynamically driven by both enthalpy (ΔH=-6.79 kcal mol ) and entropy (TΔS=1.21 kcal mol ). For the first time, a dramatic inhibition of keto-enol tautomerism of the carbonyl α-hydrogen of ALA has been observed, as evidenced by over an order of magnitude decrease of both the first step rate constant, k , and the second step rate constant, k , during hydrogen/deuterium exchange in D O. Meanwhile, as expected, the reactivity of C2-hydrogen was also inhibited significantly, with an upshift of 2.09 pK units. This discovery will not only provide an emerging host molecule to modulate keto-enol tautomerism, but also potentially lead to a novel supramolecular formulation of AGE-breaker ALA for improved stability and therapeutic efficacy.

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Keto–Enol Tautomerism in Enzymatic Reactions

Cited by 9 publications

References 85 publications

Kinetic, Crystallographic, and Mechanistic Characterization of TomN: Elucidation of a Function for a 4-Oxalocrotonate Tautomerase Homologue in the Tomaymycin Biosynthetic Pathway

Kinetic, Crystallographic, and Mechanistic Characterization of TomN: Elucidation of a Function for a 4-Oxalocrotonate Tautomerase Homologue in the Tomaymycin Biosynthetic Pathway

The chemical versatility of the β–α–β fold: Catalytic promiscuity and divergent evolution in the tautomerase superfamily

Encapsulation of AGE‐Breaker Alagebrium by Cucurbit[7]uril Improved the Stability of Both Its Carbonyl α‐Hydrogen and Thiazolium C2‐Hydrogen

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