5-Fluorolysine as alternative substrate of lysine 5,6-aminomutase: A computational study

Maity, Amarendra Nath; Ke, Shyue-Chu

doi:10.1016/j.comptc.2013.08.007

Cited by 5 publications

(5 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have recently investigated the case of 5-fluorolysine as an alternative substrate in the reaction of 5,6-LAM and found that the substrate related radical (5-FS • ) could be detected [ 99 ]. In addition, we prepared an inventory of 19 F HFCCs, originating from significant amount of spin density on fluorine nucleus ( I = 0.5), using various relevant combinations of methods, MP2 and DFT, and basis sets.…”

Section: Mechanistic Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Large-Scale Domain Motions and Pyridoxal-5'-Phosphate Assisted Radical Catalysis in Coenzyme B12-Dependent Aminomutases

Maity

Chen

2014

IJMS

Self Cite

View full text Add to dashboard Cite

Lysine 5,6-aminomutase (5,6-LAM) and ornithine 4,5-aminomutase (4,5-OAM) are two of the rare enzymes that use assistance of two vitamins as cofactors. These enzymes employ radical generating capability of coenzyme B12 (5′-deoxyadenosylcobalamin, dAdoCbl) and ability of pyridoxal-5′-phosphate (PLP, vitamin B6) to stabilize high-energy intermediates for performing challenging 1,2-amino rearrangements between adjacent carbons. A large-scale domain movement is required for interconversion between the catalytically inactive open form and the catalytically active closed form. In spite of all the similarities, these enzymes differ in substrate specificities. 4,5-OAM is highly specific for d-ornithine as a substrate while 5,6-LAM can accept d-lysine and l-β-lysine. This review focuses on recent computational, spectroscopic and structural studies of these enzymes and their implications on the related enzymes. Additionally, we also discuss the potential biosynthetic application of 5,6-LAM.

show abstract

Section: Mechanistic Studiesmentioning

confidence: 99%

“…As mentioned above (Section 6.4. ), 5-fluorolysine has the potential to accumulate the corresponding substrate radical in the steady state [ 99 ]. This analog has four different diastereomers, which can be separated by chemical modification and chiral chromatography [ 111 ].…”

Section: Outlook and Perspectivesmentioning

confidence: 99%

Large-Scale Domain Motions and Pyridoxal-5'-Phosphate Assisted Radical Catalysis in Coenzyme B12-Dependent Aminomutases

Maity

Chen

2014

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…DFT has been used to study the transitions between the conformational states of 5,6-LAM [17] and 4,5-OAM [18]. We have recently investigated the case of 5-fluorolysine as an alternative substrate in the reaction of 5,6-LAM and found that the substrate related radical (5-FS Å ) could be detected [19]. In this work, following the protocol used by Radom [15,16] and co-workers we have performed calculations on models of radical intermediates expected from the reaction of 4 0 -cyanoPLP and 5,6-LAM.…”

Section: Introductionmentioning

confidence: 98%

4′-CyanoPLP presents better prospect for the experimental detection of elusive cyclic intermediate radical in the reaction of lysine 5,6-aminomutase

Maity

2015

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

“…The N1 of the pyridine ring of PLP is not protonated. The structure of substrate d -lysine was not truncated. , We used tetrahydro-5-methylfuran-3,4-diol as a model for 5′-deoxyadenosine (dAdOH). Geometry optimizations were performed in gas phase at the B3-LYP level with 6-31G(d,p) basis.…”

Section: Methodsmentioning

confidence: 99%

“…In the case of 5,6-LAM, the substrate-related radical was detected , using a substrate analog 4-thialysine and later unambiguously characterized using labeled 4-thialysines. − High-energy intermediate I • has been eluding experimental detection. DFT computations have been playing complementary roles in the research for radical aminomuatses. ,,− Radom and co-workers proposed analogs of PLP having substitution at the 4′-carbon with π acceptors, such as vinyl and acetylenyl are promising candidates for experimental observation of the corresponding I • . Moreover, our recent results predict that another π acceptor cyano substitution offers better prospect for the same purpose .…”

Section: Introductionmentioning

confidence: 99%

Reaction of Pyridoxal-5′-phosphate-N-oxide with Lysine 5,6-Aminomutase: Enzyme Flexibility toward Cofactor Analog

et al. 2015

Self Cite

View full text Add to dashboard Cite

Lysine 5,6-aminomutase (5,6-LAM) is a 5′-deoxyadenosylcobalamin and pyridoxal-5′-phosphate (PLP) codependent radical enzyme that can accept at least three substrates, d-lysine, l-β-lysine and l-lysine. The reaction of 5,6-LAM is believed to follow an intramolecular radical rearrangement mechanism involving formation of a cyclic azacyclopropylcarbinyl radical intermediate (I•). Similar I•s are also proposed for other radical aminomutases, such as ornithine 4,5-aminomutase (4,5-OAM) and lysine 2,3-aminomutase (2,3-LAM). Nevertheless, experimental proof in support of the participation of I• have been elusive. PLP is proposed to lower the energy of this elusive I• by captodative stabilization and spin delocalization. In this work, we employ PLP-N-oxide (PLP-NO) to investigate the flexibility of 5,6-LAM toward cofactor analog and participation of I• in the reaction mechanism. Our calculations show that substitution of PLP-NO for PLP stabilizes I• by 35.2 kJ mol–1 as a result of enhanced spin delocalization, which becomes the lowest energy state along the reaction sequence. Kinetic parameters and spectroscopic observations for PLP-NO similar to those of PLP demonstrate that PLP-NO mimics natural cofactor for 5,6-LAM. Interestingly, the flexibility of 5,6-LAM toward cofactor analog PLP-NO makes it an even more promising candidate for biocatalytic applications. Expectedly, the catalytic efficiency (k cat/K m) is reduced by ∼3 times with PLP-NO as a cofactor. Various factors, including higher stabilization of proposed corresponding I• for PLP-NO than that of PLP, could lead to the decrease in activity.

show abstract

5-Fluorolysine as alternative substrate of lysine 5,6-aminomutase: A computational study

Cited by 5 publications

References 58 publications

Large-Scale Domain Motions and Pyridoxal-5'-Phosphate Assisted Radical Catalysis in Coenzyme B12-Dependent Aminomutases

Large-Scale Domain Motions and Pyridoxal-5'-Phosphate Assisted Radical Catalysis in Coenzyme B12-Dependent Aminomutases

4′-CyanoPLP presents better prospect for the experimental detection of elusive cyclic intermediate radical in the reaction of lysine 5,6-aminomutase

Reaction of Pyridoxal-5′-phosphate-N-oxide with Lysine 5,6-Aminomutase: Enzyme Flexibility toward Cofactor Analog

Contact Info

Product

Resources

About