Hydrogen Atom Transfers in B
            <sub>12</sub>
            Enzymes

Banerjee, Ruma; Truhlar, Donald G.; Dybała-Defratyka, Agnieszka; Paneth, Piotr

doi:10.1002/9783527611546.ch48

Cited by 4 publications

(3 citation statements)

References 89 publications

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“…The movement of one hydrogen atom and one electron concurrently from one orbital to another, or hydrogen atom transfer (HAT), is a fundamental reaction in the reactivity of organic molecules. [1][2][3][4][5][6][7][8] From the oxidation of biomolecules by cytochrome P450 enzymes 9 to an impressive array of earth abundant metal catalyzed reductive hydrofunctionalization reactions, 1,8 this elementary step is ubiquitous and essential to achieve otherwise challenging transformations. Despite these disparate applications, HAT reactions are all underpinned by the same general reactivity principles.…”

Section: Introduction and Theorymentioning

confidence: 99%

Cooperative Hydrogen Atom Transfer: From Theory to Applications

Kattamuri¹,

West²

2021

Synlett

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Hydrogen atom transfer (HAT) is one of the fundamental transformations of organic chemistry, allowing for the interconversion of open and closed shell species through the concerted movement of a proton an electron. While the value of this transformation is well-appreciated in isolation, allowing for homolytic C–H activation via abstractive HAT and radical reduction via donative HAT, cooperative HAT (cHAT) reactions, where two hydrogen atoms are removed or donated to vicinal reaction centers in succession proceeding through radical intermediates, are comparatively unknown outside of the mechanism of desaturase enzymes. This tandem reaction scheme has important ramifications in the thermochemistry of each HAT, with the bond dissociation energy of the C–H bond adjacent to the radical center being significantly lowered compared to that of the parent alkane, allowing for each HAT to be performed by different species. Here we discuss the thermodynamic basis of this bond strength differential in cHAT and demonstrate its use as a design principle in organic chemistry for both dehydrogenative (application 1) and hydrogenative (application 2) reactions. Together, we hope that this overview will highlight the exciting reactivity possible with cHAT and inspire further development using this mechanistic approach.

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Section: Introduction and Theorymentioning

confidence: 99%

Cooperative Hydrogen Atom Transfer: From Theory to Applications

Kattamuri¹,

West²

2021

Synlett

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“…The observation of very large hydrogen/deuterium (H/D) KIEs for hydrogen radical transfer to or from dAdo⅐ in several enzymes (5,(12)(13)(14)(15) raises the possibility that tunneling may be a common catalytic strategy for such translocation. Confirmation of this interpretation presently is best achieved by atomistic simulation of the KIEs because, despite considerable experimental attention, some key mechanistic details remain unclear (4,16).…”

mentioning

confidence: 99%

“…Therefore, the measured KIE should correspond to step 2. The most probable reason for the differing conclusions seems to be the extreme sensitivity of the system to the size of the model and the details of the dynamical model (5,16,21). Our experience indicates that only inclusion of a substantial part of the enzyme environment yields results that are pertinent to the enzymecatalyzed reaction (22).…”

mentioning

confidence: 99%

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B₁₂-dependent mutase

Dybała-Defratyka

Paneth

Banerjee

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Hydrogen transfer reactions catalyzed by coenzyme B12-dependent methylmalonyl-CoA mutase have very large kinetic isotope effects, indicating that they proceed by a highly quantal tunneling mechanism. We explain the kinetic isotope effect by using a combined quantum mechanical/molecular mechanical potential and semiclassical quantum dynamics calculations. Multidimensional tunneling increases the magnitude of the calculated intrinsic hydrogen kinetic isotope effect by a factor of 3.6 from 14 to 51, in excellent agreement with experimental results. These calculations confirm that tunneling contributions can be large enough to explain even a kinetic isotope effect >50, not because the barrier is unusually thin but because corner-cutting tunneling decreases the distance over which the system tunnels without a comparable increase in either the effective potential barrier or the effective mass for tunneling.enzyme kinetics ͉ kinetic isotope effects ͉ quantum dynamics ͉ molecular modeling ͉ ensemble-averaged variational transition state theory T he determination of the crystal structure of coenzyme B 12 or 5Ј-deoxyadenosylcobalamin (AdoCbl) by Lenhart and Hodgkin (1) revealed, unexpectedly at the time, a cobalt-carbon bond to C5Ј of the deoxyadenosyl ligand. Homolytic rupture of this bond is a key step in the carbon-skeletal rearrangements catalyzed by AdoCbl-dependent enzymes (2, 3), although atomistic details of the mechanism have remained elusive. B 12 -dependent rearrangements play vital roles in amino acid catabolism and fermentation, and methylmalonyl-CoA mutase (MMCM) is the only B 12 -dependent isomerase that is found in both mammals and bacteria. MMCM catalyzes the rearrangement of methylmalonyl-CoA to succinyl-CoA, which then can enter the Krebs cycle. An anomalously large kinetic isotope effect (KIE) has been observed for the hydrogen atom transfer from substrate to the deoxyadenosyl radical (dAdo⅐) in the step that initiates the isomerization reaction in the enzyme (4). This KIE poses a challenge to theoretical understanding (5), and we use it here as a key to elucidating atomistic details of the reaction catalyzed by MMCM.Recent advances in computational enzyme kinetics have allowed for a detailed understanding of how many enzymes work, and it now is appreciated that enzyme-catalyzed proton and hydride transfer reactions often occur by quantum mechanical tunneling (6, 7). Hydrogen atom transfers are more elusive because they often proceed by proton-coupled electron transfer. However, B 12 -dependent isomerases and reductases are believed to operate by radical translocation (3, 8-11), and various substrate and product radical intermediates have been detected by EPR spectroscopy in these enzymes. The observation of very large hydrogen/deuterium (H/D) KIEs for hydrogen radical transfer to or from dAdo⅐ in several enzymes (5, 12-15) raises the possibility that tunneling may be a common catalytic strategy for such translocation. Confirmation of this interpretation presently is best achieved by atomistic simulati...

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Shedding light on the strength, nature, and cooperativity/anti-cooperativity between intermolecular H…N hydrogen and Cl…C halogen bonds in the competitive binary and ternary complexes

Emamian,

Salami,

Javad Hosseini

2024

Computational and Theoretical Chemistry

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Hydrogen Atom Transfers in B ₁₂ Enzymes

Cited by 4 publications

References 89 publications

Cooperative Hydrogen Atom Transfer: From Theory to Applications

Cooperative Hydrogen Atom Transfer: From Theory to Applications

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B₁₂-dependent mutase

Shedding light on the strength, nature, and cooperativity/anti-cooperativity between intermolecular H…N hydrogen and Cl…C halogen bonds in the competitive binary and ternary complexes

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Hydrogen Atom Transfers in B 12 Enzymes

Cited by 4 publications

References 89 publications

Cooperative Hydrogen Atom Transfer: From Theory to Applications

Cooperative Hydrogen Atom Transfer: From Theory to Applications

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B12-dependent mutase

Shedding light on the strength, nature, and cooperativity/anti-cooperativity between intermolecular H…N hydrogen and Cl…C halogen bonds in the competitive binary and ternary complexes

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Hydrogen Atom Transfers in B ₁₂ Enzymes

Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B₁₂-dependent mutase