The Catalysis of the 1,1-Proton Transfer by α-Methyl-acyl-CoA Racemase Is Coupled to a Movement of the Fatty Acyl Moiety Over a Hydrophobic, Methionine-rich Surface

Bhaumik, Prasenjit; Schmitz, W.; Hassinen, Antti; Hiltunen, J. Kalervo; Conzelmann, Ernst; Wierenga, Rik K.

doi:10.1016/j.jmb.2007.01.062

Cited by 39 publications

(108 citation statements)

References 57 publications

(62 reference statements)

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“…As demonstrated [16,17] for M. tuberculosis and human homologues, AMACR catalyses the chiral inversion of (2R)-and (2S)-2-methylacyl-CoA through a 1,1-proton transfer mechanism. 2-Methylacyl-CoA undergoes deprotonation and forms a planar enolate with His 122 (number refer to human AMACR IA) acting as a base to deprotonate the substrate, followed by addition of H + with Asp 152 as a proton donor (Scheme 2 A).…”

Section: Resultsmentioning

confidence: 91%

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New Molecular Markers for Prostate Tumor Imaging: A Study on 2‐Methylene Substituted Fatty Acids as New AMACR Inhibitors

Morgenroth

Urusova

Dinger

et al. 2011

Chemistry A European J

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The development of prostate carcinoma is associated with alterations in fatty acid metabolism. α-Methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)-isomers of a range of α-methylacyl-CoA thioesters. AMACR is involved in the β-oxidation of the dietary branched-chain fatty acids and bile acid intermediates. It is highly expressed in prostate (more than 95 %), colon (92 %), and breast cancers (44 %) but not in the respective normal or hyperplastic tissues. Thus, targeting of AMACR could be a new strategy for molecular imaging and therapy of prostate and some other cancers. Unlabeled 2-methylenacyl-CoA thioesters (12 a-c) were designed as AMACR binding ligands. The thioesters were tested for their ability to inhibit the AMACR-mediated epimerization of (25R)-THC-CoA and were found to be strong AMACR inhibitors. Radioiodinated (E)-(131) I-13-iodo-2-methylentridec-12-enoic acid ((131) I-7 c) demonstrated preferential retention in AMACR-positive prostate tumor cells (LNCaP, LNCaP C4-2wt and DU145) compared with both AMACR-knockout LNCaP C4-2 AMACR-siRNA and benign BPH1 prostate cell lines. A significant protein-bound radioactive fraction with main bands at 47 (sum of molecular weights of AMACR plus 12 c), 70, and 75 kDa was detected in LNCaP C4-2 wt cells. In contrast, only negligible amounts of protein-bound radioactivity were found in LNCaP C4-2 AMACR-siRNA cells.

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Section: Resultsmentioning

confidence: 91%

“…A) Proposed [16,17] intermediate for the AMACR-catalyzed epimerization. B) Hypothetical mechanisms of possible AMACR inhibition by 2-methylenacyl-CoA thioesters.…”

Section: Resultsmentioning

confidence: 99%

New Molecular Markers for Prostate Tumor Imaging: A Study on 2‐Methylene Substituted Fatty Acids as New AMACR Inhibitors

Morgenroth

Urusova

Dinger

et al. 2011

Chemistry A European J

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“…The (S)-enantiomer was modeled by truncating (2S)-methylmyristoyl-CoA in the positions of four and six backbone atoms away from Ca in each side, respectively. His126 and Asp156 are proposed to be the acid/base-pair residues [15]. The protonation states of His126 and Asp156 are both neutral, and the reason for this was well-illustrated in previous studies [15].…”

Section: Quantum-chemical Modelmentioning

confidence: 59%

“…The active site catalytic residues are conserved in human AMACR [14]. This work focuses on the mechanism of AMACR, and it is on the basis of crystallographic structure of MCR (PDB: 2GD0) [15]. The main features of the active site of this structure are shown in Figure 1.…”

mentioning

confidence: 99%

“…The side chain of Ile16 and Gly17 cover the sulfur atom of the CoA moiety. Based on the structure analysis, Bhaumik et al [15] proposed the mechanism of MCR, which shown in Figure 2. The catalytic process of MCR involves a planar intermediate resulting from the deprotonation of (2S)-methylacyl-CoA, that is, the general base residue His126 abstracts a proton from (2S)-methylacyl-CoA, leading to the formation of an intermediate, subsequently, Asp156 acting as the general acid residue donates the proton on carboxyl to the intermediate and the interconversion to (2R)-methylacyl-CoA is completed.…”

mentioning

confidence: 99%

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Quantum chemical modeling of 1,1‐proton transfer reaction catalyzed by a cofactor‐independent α‐methylacyl‐CoA racemase

Zheng

Zhang

2011

Int J of Quantum Chemistry

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a-Methylacyl-CoA racemases (AMACR) are essential enzymes for branched-chain lipids and drugs metabolism. AMACR catalyzes the chiral inversion of (2R) and (2S)-methylacyl-CoA esters in both directions. In this study, we investigated the catalytic mechanism of Mycobacterium tuberculosis (MCR) amethylacyl-CoA racemase by using the density functional theory with the hybrid functional B3LYP. Our calculations elucidate and support the mechanism proposed by Prasenjit Bhaumik. His126 and Asp156 serve as the acid/base-pair residues in the 1,1-proton transfer catalytic reaction. From the optimized structures, it can be seen that an enolate intermediate is formed and the possibility of forming a ketene or a carbanion intermediate is excluded. By comparing the energy barriers, we could consider that the deprotonation step is the rate-determined step in the invert direction from (S)-to (R)-enantiomer.

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Stereochemische Untersuchungen enthüllen den Mechanismus der sauerstofffreien Aktivierung von n‐Alkanen durch Bakterien

et al. 2011

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Während des anaeroben Wachstums des Bakterienstamms HxN1 entstehen nahezu gleiche Mengen an (2R,1′R)‐ und (2S,1′R)‐(1‐Methylpentyl)succinat, die durch radikalische Addition des Kohlenwasserstoffs an Fumarat gebildet werden (siehe Schema). Der hochselektive Angriff auf das proS‐Wasserstoffatom an C2 des n‐Hexans geht mit der Inversion der Konfiguration an C2 während der Bindungsknüpfung mit dem Fumarat einher und ist mit einer Isotopendiskriminierung gegen eine C‐2H‐Bindung verbunden.

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The Catalysis of the 1,1-Proton Transfer by α-Methyl-acyl-CoA Racemase Is Coupled to a Movement of the Fatty Acyl Moiety Over a Hydrophobic, Methionine-rich Surface

Cited by 39 publications

References 57 publications

New Molecular Markers for Prostate Tumor Imaging: A Study on 2‐Methylene Substituted Fatty Acids as New AMACR Inhibitors

New Molecular Markers for Prostate Tumor Imaging: A Study on 2‐Methylene Substituted Fatty Acids as New AMACR Inhibitors

Quantum chemical modeling of 1,1‐proton transfer reaction catalyzed by a cofactor‐independent α‐methylacyl‐CoA racemase

Stereochemische Untersuchungen enthüllen den Mechanismus der sauerstofffreien Aktivierung von n‐Alkanen durch Bakterien

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