(8,9). A number of investigators have found that the level of MAO B in preparations exhibiting high affinity sites is only 5-10% of the total enzyme present (9 -11). It is not known whether this high affinity binding also results in enzyme inhibition. To date, no molecular explanation has been found to resolve these observations except to propose that the nanomolar binding site is separate from the active site and is possessed by a subpopulation of enzyme occurring by an unknown mechanism. No evidence exists for any altered enzyme forms (alternate splicing or posttranslational modification(s)), which might account for the observed substoichiometric levels of high affinity binding sites on MAO B.The Eli Lilly group (11-13) observed that inhibition of human MAO B by tranylcypromine increases the level of high affinity I 2 -binding sites from 5-10% to ϳ90% of the total enzyme. This potentiation is observed with MAO B in human platelets, in membrane preparations from human cortex, and from medulla preparations as well as with membrane particles of human recombinant MAO B (but not with human MAO A) expressed in insect cells (13). These data suggest that inhibition of MAO B by tranylcypromine alters the enzyme to a form that * This work was supported, in whole or in part, by National Institutes of Health Grant GM 29433 (to D. E. E.) and a predoctoral fellowship from the National Institutes of Health through NINDS Award F31NS063648 (to E. M. M.). This work was also supported by grants from the Fondazione Cariplo (to D. E. E. and A. M.), , and Canadian Institutes of Health Research (Grant MOP77529) to A. H. The atomic coordinates and structure factors (codes 2XFU, 2XCG, 2XFN, 2XFO, 2XFP, and 2XFQ) The abbreviations used are: MAO, monoamine oxidase; 2-BFI, 2-(2-benzofuranyl)-2-imidazoline.
C À H bond amination has emerged as a powerful tool for the synthesis of complex nitrogen-containing molecules. Following the early discoveries by Breslow and Gellman, [1] Du Bois and co-workers revolutionized this area of chemistry by developing protocols for practical, efficient, and predictable reactions for oxidative C À H amination.[2] Dirhodium(II) tetracarboxylate catalysts were shown to be particularly effective. Manganese-and ruthenium-porphyrin complexes, [3] silver complexes, [4] and preoxidized nitrogen sources have also been developed as catalysts to carry out this important reaction. [5] Despite these recent advances, general methods for both enantioselective and intermolecular C À H amination remain elusive. Although chiral dirhodium(II) complexes have been developed as catalysts for highly enantioselective metallocarbene reactions, [6] their application to CÀH amination chemistry is yet to produce the same spectacular results. [7] To date, the most effective protocol for asymmetric CÀH amination requires the combination of enantioenriched sulfoxamines as chiral auxiliaries and a chiral dirhodium(II) catalyst.[8] To address the challenge of catalytic asymmetric CÀH amination, we chose to study ruthenium(II)-pybox (pybox = pyridine bisoxazoline) complexes (Scheme 1). Despite reports that show complex 1 exhibited limited reactivity and selectivity in C À H amination reactions, [3f] we felt that the modular nature of the ligand, and the fact that the anionic ligands were independent of the chiral pybox ligand, offered us an opportunity which had not been possible by using either dirhodium(II)-or porphyrin-based catalyst systems.Ruthenium(II)-pybox complexes 1-4 were readily prepared by using the method developed by Nishiyama et al. (Scheme 1).[9] In our initial study, the challenging test substrate sulfamate ester 5[10] was treated with 1.1 equivalents of the oxidant bis(acetoxy)iodobenzene and 5 mol % catalyst 2 to give the desired product of CÀH insertion 6, albeit in modest yield and enantiomeric excess (Table 1, entries 1-3).Based on the study by Fiori and Du Bois, which demonstrates that rhodium-catalyzed C À H amination involves formation of an electrophilic metallonitrene and a build up of positive charge on the carbon center during the insertion process, we rationalized that a cationic catalyst would be more reactive than its neutral analogue.[2e] Halide abstraction from the Scheme 1. Synthesis of ruthenium(II)-pybox complexes. [b] ee [%] [b]
Summary The major structural difference between human monoamine oxidases A (MAO A) and B (MAO B) is that MAO A has a monopartite substrate cavity of ~550 Å3 volume and MAO B contains a dipartite cavity structure with volumes of ~290 Å3 (entrance cavity) and ~400 Å3 (substrate cavity). Ile199 and Tyr326 side chains separate these two cavities in MAO B. To probe the function of these gating residues, Ile199Ala and Ile199Ala Tyr326Ala mutant forms of MAO B were investigated. Structural data on the Ile199Ala MAO B mutant show no alterations in active site geometries compared to WT enzyme while the Ile199Ala-Tyr326Ala MAO B mutant exhibits alterations in residues 100–103 which are part of the loop gating the entrance to the active site. Both mutant enzymes exhibit catalytic properties with increased amine KM but unaltered kcat values. The altered KM values on mutation are attributed to the influence of the cavity structure in the binding and subsequent deprotonation of the amine substrate. Both mutant enzymes exhibit weaker binding affinities relative to WT enzyme for small reversible inhibitors. Ile199Ala MAO B exhibits an increase in binding affinity for reversible MAO B specific inhibitors which bridge both cavities. The Ile199Ala-Tyr326Ala double mutant exhibits inhibitor binding properties more similar to those of MAO A than to MAO B. These results demonstrate the bipartite cavity structure in MAO B plays an important role in substrate and inhibitor recognition to distinguish its specificities from those of MAO A and provides insights into specific reversible inhibitor design for these membrane-bound enzymes.
The field of protein conjugation most commonly refers to the chemical, enzymatic, or chemoenzymatic formation of new covalent bonds between two polypeptides, or between a single polypeptide and a new molecule (polymer, small molecule, nucleic acid, carbohydrate, etc.). Due to the modest selectivity of chemical methods for protein conjugation, there are increased efforts to develop biocatalysts that confer regioselectivity for site-specific modification, thereby complementing the existing toolbox of chemical conjugation strategies. This review summarizes key advances in the use of enzymes to functionalize proteins with commercial relevance. The examples put forth have demonstrated value at the industrial level or show promising industrial potential in the laboratory.
Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors. KeywordsMonoamine oxidase A; Monoamine oxidase B; Reversible inhibitor; Isatin; (E)-5-Styrylisatin; (E)-6-StyrylisatinThe oxidative deamination reaction catalyzed by monoamine oxidase B (MAO-B) is one of the major catabolic pathway of dopamine in the brain. Inhibitors of this enzyme lead to enhanced dopaminergic neurotransmission and are currently used in the symptomatic treatment of Parkinson's disease (PD). 1-4 Furthermore, MAO-B inhibitors also may exert a neuroprotective effect by reducing the concentrations of potentially hazardous by-products produced by MAO-B-catalyzed dopamine oxidation. 5 Considering that the human brain exhibits an age-related increase in MAO-B activity, inhibition of this enzyme is especially relevant in the treatment of PD. 6-8 The endogenous small molecule isatin (1) (Fig. 1) has been reported to be a moderately potent inhibitor of human MAO-B with an enzyme-inhibitor *Corresponding author. Tel.: +27 18 2992206; fax: +27 18 2994243. E-mail adress: E-mail: jacques.petzer@nwu.ac.za (J.P. Petzer). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Another small molecule, caffeine (2), is a weak inhibitor of MAO-B with a K i value of 3.6 mM. The inhibition potency of caffeine is substantially increased by substitution at C-8 of the caffeinyl ring with a styryl...
An enantioselective synthesis of the potent anti-HIV nucleoside EFdA is presented. Key features of stereocontrol include construction of the fully substituted 4'-carbon via a biocatalytic desymmetrization of 2-hydroxy-2-((triisopropylsilyl)ethynyl)propane-1,3-diyl diacetate and a Noyori-type asymmetric transfer hydrogenation to control the stereochemistry of the 3'-hydroxyl bearing carbon. The discovery of a selective crystallization of an N-silyl nucleoside intermediate enabled isolation of the desired β-anomer from the glycosylation step.
Flavins and related molecules catalyze organic Baeyer−Villiger reactions. Combined experimental and DFT studies indicate that these molecules also catalyze the insertion of oxygen into metal−carbon bonds through a Baeyer−Villiger-like transition state.S elective oxy functionalization reactions are among the most important classes of chemical transformations for both biological and nonbiological processes. In contrast to the broad progress on oxygen transfer reactions for olefins, 1 significant barriers remain for the development of catalysts for the selective partial oxidation of saturated hydrocarbons. 2 Transition-metal-mediated partial oxidation of alkanes involves two key steps: C−H bond cleavage and C−O bond formation. In the Pt-based Shilov reaction and related systems, 3 C−H activation occurs at Pt II , and C−O bond formation likely involves a nucleophilic addition to an electrophilic hydrocarbyl coordinated to Pt IV . The required formal two-electron redox sequence between Pt II and Pt IV has limited further development of this process, since scalable reactions with practical oxidants have not been developed. 3,4 A potential alternative to the Shilov pathway for partial oxidation of alkanes is shown in Scheme 1. 5 In this pathway, a metal alkoxide complex activates a C−H bond for 1,2-addition across the M−OR bond to form a metal hydrocarbyl complex and a free alcohol. Insertion of an oxygen atom into the M−R bond reforms the initial alkoxide complex.The 1,2-addition of C−H bonds across metal−heteroatom bonds is known. In 2004, we reported intramolecular C−H activation by a parent Ru II amido complex 6 followed by intermolecular C−H activation of benzene by Ru II hydroxide and anilido complexes. 7 Similar reactions of Ir III , 8 Rh I , 9 and other Ru II complexes 10 have also been observed and extensively modeled. 11 Although limited in number, examples of insertion of an oxygen atom into M−C bonds are also known. Insertion of an oxo ligand into a Re−Ph bond of a cationic Re VII complex has been observed. 12 A similar mechanism has been proposed for several Pd complexes. 13 Hillhouse and co-workers have studied the transfer of oxygen from N 2 O into the Ni−alkyl and Ni−aryl bonds of Ni II metallacycles. 14 Methylrhenium trioxide (MTO) reacts with oxidants to produce methanol. 15 Goddard, Periana, and co-workers 16 proposed a reaction pathway similar to the organic Baeyer− Villiger (BV) reaction that proceeds by coordination of the oxidant (YO) and subsequent methyl migration and loss of Y (Scheme 2 for YO = HOO − ). Related reactions of arylrhenium trioxides have been studied. 17 However, theoretical studies have indicated that the activation barrier for this pathway can be high, especially for late-transition-metal complexes. 18 Thus, the implementation of a combined C−H activation/oxygen insertion strategy for catalytic hydrocarbon oxidation depends on uncovering methods for lowering the activation barrier for oxygen insertion into metal−hydrocarbyl bonds. This work led us to consider...
Playing a pivotal role in the metabolism of neurotransmitters in the central nervous system, the mitochondrial enzymes monoamine oxidases A and B (MAO A and B) have been for long studied as drug targets for neurodegenerative and neurological diseases. MAO inhibitors (MAOIs) are clinically used to treat Parkinson's disease and depression by blocking the degradation of neuroactive catecholamines and providing a symptomatic relief in the patients. More recent is the idea that the neuroprotective effect of MAOIs may result from the prevention of oxidative stress produced by the MAO reaction rather than being simply related to the inhibition of neurotransmitters degradation. Tranylcypromine and phenelzine are among the first developed MAOI drugs and have been used for years to treat depression. Their usage is now limited to cases of refractory depression because of their negative side effects, which are due to both the lack of MAO A/MAO B selectivity and the inhibition of other enzymes such as the drug-metabolizing cytochromes P450. Although the multi-target action of these MAOIs determines negative implications, the most newly developed compounds have improved properties not only for their specificity relatively to MAO A/MAO B selectivity but also because they function through multiple mechanisms that produce beneficial effects. In particular, safinamide, a MAO B selective inhibitor in clinical trials for Parkinson's disease, is neuroprotective by blocking the voltage-dependent Na+ and Ca2+ channels and the Ca2+-mediated glutamate release processes. Rasagiline is a drug used in combination with L-dopa in the treatment of parkinsonian patients and the metabolic products of its degradation exert neuroprotective effects. Moreover, rasagiline scaffold is used to design analogs by addition of pharmacophores that act on other neurological targets. This multi-target approach may prove successful in order to find new and more effective therapies for the complexity of neurodegenerative diseases.
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