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Enzymes are proteins that function as catalysts for biological reactions. A catalyst is a substance that accelerates a chemical reaction without itself undergoing any net change. The types of chemical reactions that can be catalyzed by proteins alone are limited by the chemical properties of the functional groups found in the side chains of nine amino acids:1 the imidazole ring of histidine, the carboxyl groups of glutamate and aspartate, the hydroxyl groups of serine, threonine, and tyrosine, the amino group of lysine, the guanidinium group of arginine, and the sulfhydryl group of cysteine. These groups can act as general acids and bases in catalyzing proton transfers and as nucleophilic catalysts in group transfer reactions.
However, many metabolic reactions involve chemical changes that cannot be brought about by the structures of the amino acid side chain functional groups in enzymes acting by themselves. In catalyzing these reactions, enzymes must act in cooperation with coenzymes which are smaller organic molecules or metallic cations and possess special chemical reactivities or structure properties that are useful for catalyzing reactions. Most coenzymes are derivatives of the water-soluble vitamins, but a few, such as hemes, lipoic acid, and iron-sulfur clusters, are biosynthesized in the body. Each coenzyme plays a unique chemical role in the enzymatic processes of living cells.
The two important characteristics of enzyme catalysis are the selectivity and rate acceleration. It has been recognized that an enzyme has three levels of selectivity: structural selectivity, regioselectivity, and stereoselectivity. An enzyme must first recognize some common structural features present on a substrate (and coenzyme) to produce catalysis. Second, catalysis must occur at a specific region on the substrate (or the coenzyme ) and the stereochemical outcome must be controlled by the enzyme.
The function of a catalyst is to provide a new reaction pathway in which the rate determining step has a lower energy of activation than the rate-determining step of the uncatalyzed reaction. An enzyme has many ways to invoke catalysis, for example, by destabilization of the enzyme substrate complex, by stabilization of the transition states and by destabilization of intermediates. Consequently, multiple steps, each having small âˆ†G values, may be involved. This is responsible for the rate acceleration results.
B. Flavin coenzymes
Flavin coenzymes act as co-catalysts with enzymes in a large number of redox reactions, many of which involve O2.2 Flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) are the coenzymatically active forms of vitamine B2, riboflavin (Figure 1.1).
Figure 1.1. Structures of the Vitamin Riboflavin and the Derived Flavin Coenzymes
Riboflavin is the N10-ribitylisoalloxazine portion of FAD, which is enzymatically converted into its coenzymatic forms first by phosphorylation of the ribityl C-5' hydroxyl group to FMN and then by adenlylation to FAD. FMN and FAD are functionally equivalent coenzymes and the one that is involved with a given enzyme appears to be a matter of enzymatic binding specificity.
The catalytically functional portion of the coenzymes is the isoalloxazine ring, specifically the N-5 and C-4a positions, which is thought to be the immediate locus of catalytic function. Even so, the entire chromophoric system extending over N-5, C-4a, C-10a, N-1, and C-2 should be regarded as an indivisible catalytic entity.
Figure 1.2. Oxidation States of Flavin Coenzymes
The flavin coenzymes exist in four spectrally distinguishable oxidation states that account in part for their catalytic functions (Figure 1.2).1 They are the yellow oxidized form, the red or blue one-electron reduced form, and the colorless two-electron reduced form.
1.1.2. Kinetics of enzyme-catalyzed reactions
A. Enzyme-catalyzed reactions
Enzymes have localized catalytic sites. The substrate (S) binds at the active site to form an enzyme-substrate complex (ES). Subsequent steps transform the bound substrate into product and regenerate the free enzyme E (Figure 1.3).
Figure 1.3. Enzyme-catalyzed Reaction
The overall speed of the reaction depends on the concentration of ES. Based on the steady-state kinetics analysis assumption, shortly after the enzyme and substrate are mixed, [ES] becomes approximately constant and remains so for a period of time, that is the steady state. The rate (Î½) of the reaction in the steady state usually has a hyperbolic dependence on the substrate concentration. It is proportional to [S] at low concentrations but approaches a maximum (Vmax) when the enzyme is fully occupied with substrate (Figure 1.4).
Figure 1.4. The Reaction Velocity as a Function of the Substrate Concentration (S) for an Enzyme-catalyzed Reaction
Vmax, the maxium velocity, is obtained when all the enzyme is in the form of the enzyme-substrate complex. Km, the Michaelis constant, is the substrate concentration at which the velocity is half maximal. If ES is in equilibrium with the free enzyme E and substrate S, Km is equal to the dissociation constant for the complex (Ks). More generally, Km depends on at least three rate constants and is larger than Ks. kcat, the turn over number, is the maximum number of molecules of substrate converted to product per active site per unit time and is Vmax divided by the total enzyme concentration. kcat/Km, the specificity constant, provides a measure of how rapidly an enzyme can work at low substrate concentration [S]. It is useful for comparing the relative abilities of different compounds to serve as substrates for the same enzyme. The bigger this number, the better the substrate.
B. The measurement of the kinetic parameters
Kinetic parameters are determined by measuring the initial reaction velocity as a function of the substrate concentration. The usual procedure for measuring the rate of an enzymatic reaction is to mix enzyme with substrate and observe the formation of product or disappearance of substrate as soon as possible after mixing, that is when the substrate concentration is still close to its initial value and the product concentration is small. The measurements usually are repeated over a range of substrate concentrations to map out how the initial rate depends on concentration. Km and Vmax often can be obtained from a plot of 1/Î½ versus 1/[S] (Figure 1.5). Spectrophotometric techniques are commonly used in such experiments to measure the concentration of a substrate or product continuously as a function of time.
Figure 1.5. The Lineweaver-Burk Double-reciprocal Plot
1.1.3. The mechanisms of enzyme catalysis
Several factors are considered when attempting to describe the mechanism by which an enzyme catalyzes a particular reaction. Among them, the most common factors are: (1) the proximity effect, (2) electrostatic effect, (3) general-acid and general-base catalysis, (4) nucleophilic or electrophilic catalysis by enzymatic functional groups, and (5) structural flexibility.
The proximity effect is due simply to differences between the entropic changes that accompany the inter- and intramolecular reactions. Enzymes that catalyze intermolecular reactions take advantage of the proximity effect by binding the reactants close together in the active site so the reactive groups are oriented appropriately for the reaction. Once the substrates are fixed in this way, the subsequent reaction behaves kinetically like an intramolecular process. The decrease in entropy associated with the formation of the transition state has been moved to an earlier step, the binding of the substrate to form the enzyme-substrate complex. This step often is driven by a decrease in enthalpy associated with electrostatic interactions between polar or charged groups of the substrates and enzyme.
Electrostatic interactions can promote the formation of the transition state. Charged, polar, or polarizable groups of the enzyme are positioned to favor the redistribution of electrical charges that occur as the substrate evolves into the transition state. The energy difference between the initial state and the transition state thus depends critically on the details of the protein structure. General-base and general-acid catalysis provide ways of avoiding the need for extremely high or low pH. The task of a catalyst is to make a potentially reactive group more reactive by increasing its intrinsic electrophilic or nucleophilic character. In many cases the simplest way to do this is to add or remove a proton.
Enzymatic functional groups provide nucleophilic and electrophilic catalysis. The basic feature of the nucleophilic and electrophilic catalysis is the formation of an intermediate state in which the substrate is covalently attached to a nucleophilic group on the enzyme. Structural flexibility can increase the selectivity of enzymes by ensuring that substrates bind or react in an obligatory order and by sequestering bound substrates in pockets that are protected from the solvent.
A. Forms of enzyme inhibition
Enzymes can be inhibited by agents that interfere with the binding of substrate or with conversion of the ES complex into products. There are two kinds of inhibitors: reversible and irreversible inhibitors. Reversible inhibition involves no covalent interactions.
Reversible inhibitors include competitive, noncompetitive, and uncompetitive inhibitors. A competitive inhibitor competes with substrate for binding at the active site. Consequently, a sufficiently high concentration of substrate can eliminate the effect of a competitive inhibitor. Noncompetitive inhibitors bind at a separate site and block the reaction regardless of whether the active site is occupied by substrate. A noncompetitive inhibitor decreases the maximum velocity of an enzymatic reaction without affecting the Km. This inhibitor removes a certain fraction of the enzyme from operation, no matter the concentration of the substrate. An uncompetitive inhibitor binds to the ES complex but not to the free enzyme. These three forms of inhibition are distinguishable by measuring the rate as a function of the concentrations of the substrate and inhibitor.
Irreversible inhibitors (inactivators) are compounds that produce irreversible inhibition of the enzyme. They often provide information on the active site by forming covalently linked complexes that can be characterized.
B. Mechanism-based inactivation
(1) The kinetics of mechanism-based inactivation
A mechanism-based inactivator is an inactive compound whose structure resembles that of either the substrate or product of the target enzyme and which undergoes a catalytic transformation by the enzyme to a species that, prior to release from the active site, inactivates the enzyme. 4
The basic kinetics are described in Figure 1.6. A mechanism-based inactivator (I) requires a step to convert the compound to the inactivating species (k2). This step, which generally is responsible for the observed time dependence of the enzyme inactivation, usually is irreversible and forms a new complex EË˜ I which can have three fates: (1) if Eâ€¢Iâ€² is not reactive, but forms a tight complex with the enzyme, then the inactivation may be the result of a non covalent tight-binding complex Eâ€¢Iâ€²; (2) if the I is a reactive species, then a nucleophilic, electrophilic, or radical reaction with the enzyme may ensure (k4) to give the covalent complex Eâ€¢Iâ€³; and (3) the species generated could be released from the enzyme as a product (k3).
Figure 1.6. The Lineweaver-Burk Double-reciprocal Plot
Based on this mechanism, the two principal kinetic constants that are useful in describing mechanism-based enzyme inactivators kinact and Ki are obtained. kinact represents the inactivation rate constant at infinite concentrations of inactivator. When k2 is rate determining and k3 is 0, kinact = k2. Ki represents the dissociation constants for the breakdown of the EI complex when kon and koff are very large.
Kinact = k2k4 / (k2 + k3 + k4) (1)
K1 = [( koff + k2) / kon ] [(k3 + k4) / (k2 + k3 + k4)] (2)
The ratio of product release to inactivation is the partition ratio and represents the efficiency of the mechanism-based enzyme inactivator. When inactivation is the result of the formation of a covalent bound adduct, the partition ratio is described by k3/k4.
(2) The experimental criteria for mechanism-based inactivation
The major experimental criteria established for the characterization of mechanismbased inactivators are as follows:
(a) There is a time-dependent loss of enzyme activity. Because following a rapid equilibrium of the formation of the EI complex, there is a slower reaction that converts the inactivator to a form that actually inactivates the enzyme (k2).
(b) Saturation kinetics are observed. The rate of inactivation is proportional to the concentration of the inactivator until sufficient inactivator is added to saturate all of the enzyme molecules.
(c) Addition of a substrate or competitive reversible inhibitor slows down the rate of enzyme inactivation. Because mechanism-based inactivators act as modified substrates, they compete with other substrates for the target enzymes and bind to the active site.
(d) Dialysis or gel filtration does not restore enzyme activity, i.e., mechanism-based inactivators form stable covalent adducts.
(e) A 1:1 stoichiometry of radio-labeled inactivator to active site usually results after inactivation followed by dialysis or gel filtration. Because mechanism-based inactivators require the catalytic machinery at the active site of the enzyme to convert them to the form that inactivates the enzyme, at most one inactivator molecule should be attached per enzyme active site.
(3) The uses of mechanism-based enzyme inactivators
There are two principal areas where mechanism-based enzyme inactivators have been most useful: (1) in the study of enzyme mechanisms and (2) in the design of new potential drugs.
Mechanism-based inactivators are modified substrates for the target enzymes. Once inside the active site of the enzymes, they are converted to products that inactivate the enzyme by the catalytic mechanism for the normal substrates. Therefore, whatever information can be obtained regarding the inactivation mechanism is directly related to the catalytic mechanism of the enzyme.5
A mechanism-based inactivator could have the desirable drug properties of specificity and low toxicity if the nonspecific reactions with other biomolecules is limited and the partition ratio is small. Since mechanism-based inactivators are unreactive compounds, there are usually no nonspecific reactions with other biomolecules. Only enzymes that are capable of catalyzing the conversion of these compounds to the form that inactivates the enzyme, and enzymes that have an appropriately positioned active site group to form a covalent bond, would be susceptible to inactivation.3
1.2. Monoamine Oxidase (MAO)
1.2.1. Compositions and locations
Monoamine oxidase (MAO) is a ubiquitous membrane-bound, flavin-containing enzyme, which is particularly abundant in the liver and brain.6 MAO is located intracellularly in the mitochondrial outer membranes of neuronal, glial, and other cells and catalyzes the oxidative deamination of monoamine neurotransmitters both from endogenous and exogenous sources to the corresponding aldehydes with consumption of oxygen and production of hydrogen peroxide, thereby affecting the concentrations of neurotransmitter amines as well as many xenobiotic ones (Figure 1.7).7-10 In mammals, two distinct isoforms of MAO are present in most tissues, namely, MAO-A and MAO-B based on their differential substrate and inhibitor specificity (Figure 1.8) 11-13, tissue and cell distribution14, and gene expression15-16.
MAO-A preferentially deaminates aromatic monoamines such as the neurotransmitters serotonin, noradrenaline, and adrenaline, while MAO-B mainly oxidizes Î²-phenylethylamines and benzylamines. Both isoforms act on dopamine and tryptamine 6
Figure 1.7: Mechanism of MAO-A and MAO-B
Figure 1.8: Substrate specificity and catalysis of MAOs
Substrate specificity and catalysis of MAOs, (a) Examples of human MAO substrates. MAO A and B have distinct but partly overlapping specificities. Benzylamine, phenethylamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are good substrates for MAO B (but are oxidized at a slower rate by MAO A), whereas serotonin is a specific substrate for MAO A. Dopamine and epinephrine are oxidized at similar catalytic efficiencies by both enzymes. (b) The oxidation of benzylamine and the reaction product. (c) Scheme for the overall oxidative deamination reaction catalyzed by MAOs. Oxidation of the amine substrate leads to the reduction of FAD. The prosthetic group is reoxidized by molecular oxygen to generate hydrogen peroxide. The imine product is hydrolyzed in a nonenzymatic process. This might lead to the production of a cytotoxic hydroxyl radical (Â·OH) and could impose oxidative stress on neurons, causing local cell death17
The first generation of MAO inhibitors, originally synthesized in the 1950s, was used as antidepressants due to their inhibitory effect on the metabolism of monoamine neurotransmitters. Following an initial experience with non-selective, irreversible MAO inhibitors in the treatment of depression associated with severe side effects like the "cheese reaction".18
The cheese reaction (Figure 1.9) is induced by tyramine and other indirectly acting sympathomimetic amines present in food (most commonly in certain cheeses, hence the name) and fermented drink, such as beer and wine. Under normal circumstances, such dietary amines are extensively metabolized by MAO in the gut wall and in the liver and they are thus prevented from entering the systemic circulation. In the presence of a MAO inhibitor, this protective system is inactivated and tyramine or other monoaminespres ent in ingested food are not metabolized and enter the circulation. From here they have access to, and induce a significant release of noradrenaline from, peripheral adrenergic neurons. The consequence of this release is a severe hypertensive response which, in some cases, can be fatal.19-20
Figure 1.9: Mechanism of Cheese Reaction
These serious side effects stimulated a search for selective inhibitors of MAO-A and MAO-B. Today the selective MAO-A inhibitors are currently used for treating neurological disorders such as anxiety and depression, while selective inhibitors of the B isoform are administered alone or together with L-DOPA for the treatment of Parkinson's syndrome and Alzheimer's disease.21
1.2.2. Structural similarity between two isoforms
The overall structure of hMAO A is quite similar to that of hMAO B (rms deviation of 1.2 Å, 488 equivalent CÎ± atoms) and that of rMAO A (rms deviation of 1.2 Å, 488 equivalent CÎ± atoms) (Figure 1.10). The only significant structural difference observed is the conformation of the cavity-shaping loop 210-216 These residues are important for the structure of the hMAO A active site and exhibit different conformations on comparison of the rat and human enzymes. Removal of these residues from the structural comparisons results in a reduced rms deviation, which decreases to 0.7 Å in the superpositions of hMAO A with hMAO B. Another unique structural feature of hMAO A is that it crystallizes as a monomer where as hMAOB which crystallize as dimers with large surface contact area between monomers (â‰ˆ15% of total monomer surface area)22
Figure 1.10: (A) Ribbon representation of the monomer. The FAD-binding domain (residues 13-88, 220-294, and 400-462) is in blue; the substrate-binding domain (89-219 and 295-399) is in red; and the C-terminal membrane region (463-506) is in green. Residues 1-12, 111-115, and 507-527 are not visible in the electron density map. A dashed line connects residues 110-116. FAD and clorgyline are depicted in yellow and cyan ball-and-stick representation, respectively. The active site cavity-shaping loop 210-216 is depicted as black coil. (B) Stereoview of the superposition of the CÎ± traces of human MAO A (black) and MAO B (red). FAD and clorgyline bound to MAO A are shown as black ball-and-stick. Loop 210-216 of hMAO A and the equivalent loop 201-206 of hMAO B are shown as thick coils to highlight their different conformations.22
Structural comparison of hMAO A with hMAO B is that it would provide the molecular foundation for the design of highly specific reversible inhibitors for each enzyme. Because clorgyline and deprenyl are biochemically the most widely used specificMAO inhibitors, we determined the structure of hMAOB after inhibition with deprenyl as a comparison with the structure of clorgylineinhibited hMAO A. Although the overall chain-folds of the two isozymes are quite similar, there are similarities and differences in their respective active sites. The structures of the covalent FAD coenzymes and the two tyrosines constituting the ''aromatic cage'' (28) in the active sites are identical.23
The putative 161-amino acid segment responsible for specificity in human MAO A and B (residues 215-375 in MAO A and 206-366 in MAO B) is aligned from mouse, rat, and bovine MAO A, mouse and rat MAO B, and trout MAO (Figure 1.11). The 15 amino acids that are nonconserved between MAO A and B subtypes and concurrently conserved among all the different species within a subtype. When trout MAO is classified as an "MAO A subtype" because of similar kinetics, the remaining five amino acids nonconserved between subtypes and conserved among the different species of a subtype are boxed. The three corresponding amino acid pairs selected for reciprocal interchange by mutagenesis are indicated above the boxed amino acids.13
Figure 1.11: Multiple sequence alignment of the putative MAO segment responsible for substrate and inhibitor specificity.
The critical amino acid replacements in the active site of hMAO A are residues Phe-208 (Ile-199 in hMAO B) and Ile-335 (Tyr-326 in hMAOB) (Table 1.1). The binding of deprenyl would have to displace Phe-208 in hMAO A, whereas bound clorgyline would collide with Tyr-326 in hMAO B. A conclusion from these structural comparisons of human MAO A and MAO B is that conversion of one form into another is a more complex process that would require more than single or double site mutations to accomplish.13
Table 1.1: Active site residues in hMAO A and B
CÎ± atoms separation, *Å
*Distance between equivalent of CÎ± atoms after superposition of the hMAO-A
structure and the complex of hMAO B with deprenyl.
1.3. Neurological Disorders
1.3.1 Parkinson's Disease
Parkinson's disease belongs to a group of conditions called movement disorders. The four main symptoms are as follows: tremor, which is trembling in hands, arms, legs, jaw, or head; rigidity, which is stiffness of the limbs and trunk; bradykinesia, which is slowness of movement; and postural instability, which is impaired balance. These symptoms begin gradually but become worse with time.Â As they become more pronounced, patients may have difficulty in talking,walking or for completing other simple tasks. Everyone with one or more of these symptoms may not have PD, as the symptoms sometimes appear in other diseases as well.
PD is both chronic, which means it persists over a long period of time, and progressive, which means its symptoms grow worse with time. It is not contagious. Some PD cases appear to be hereditary, and a few are traced to specific genetic mutations,but most cases are sporadic - that is, the disease does not seem to run in families.Â Many researchers now believe that PD results as a combination of genetic susceptibility and exposure to one or more environmental factors that trigger the disease.24
The most common type of Parkinsonism is PD,which is the name given for a group of disorders with similar features and symptoms.It is also called primary parkinsonism or idiopathic PD. The term idiopathic means a disorder for which the cause has not yet been found. Although most forms of parkinsonism are idiopathic, there are some cases where the cause is known or suspected or where the symptoms result from another disorder.Â For example, parkinsonism may be as a result of changes in the brain's blood vessel.
Parkinson's disease occurs when nerve cells in one area of the brain called the substantia nigra die or become impaired. These neurons produce dopamine,which is an important chemical messenger in the brain responsible for transmitting signals between the substantia nigra and the next "relay station" of the brain, the corpus striatum. This helps to produce smooth and purposeful movement. Loss of dopamine leads to abnormal nerve firing patterns within the brain which inturn causes impaired movement. Studies on the Parkinson's patients have shown that the symptoms appeared,when most of them have lost 60 percent or more of the dopamine-producing cells in the substantia nigra.Â
Recent studies on Parkinson's patients have shown that they also have loss of the nerve endings that produce the neurotransmitter norepinephrine. Norepinephrine is closely related to dopamine.It is the main chemical messenger of the sympathetic nervous system which controls many automatic functions of the body,for example the pulse and blood pressure. The loss of norepinephrine in Parkinson's patients helps to explain the fact of many of the non-motor features seen in PD,like fatigue and abnormalities of blood pressure regulation.
Pathways of dopamine synthesis (Figure 1.12) in dopaminergic neurons and metabolism by MAO-A and -B in the brain. Tyrosine passes through the blood-brain barrier and is hydroxylated by tyrosine hydroxylase (TH) to DOPA and then decarboxylated by DOPA decarboxylase (DDC) to dopamine (DA) within the neuron. Dopamine is taken up into synaptic vesicles (SV) or metabolized by MAO-A in neuronal mitochondria. After release from the terminal, extracellular dopamine is cleared by uptake into astrocytes and glia also containing MAO-A and MAO-B. Selective inhibition of one MAO isoform allows the other to metabolize dopamine effectively and does not alter the steady state levels of striatal dopamine.45
Figure 1.12: Pathways of dopamine synthesis in dopaminergic neurons and metabolism by MAO-A and -B in the brain.
Although the important role of genetics in PD is increasingly recognized, most researchers believe that exposure to environmental factors increase a person's risk of developing the disease. In familiar cases also, where the symptoms of the disease appear, exposure to toxins and other environmental factors may affect the progress of the disease. Examples of toxins that can cause parkinsonian symptoms in humansÂ are 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, or MPTP (found in some kinds of synthetic heroin).Â There may be still many unidentified environmental factors which may cause PD in genetically susceptible individuals.24
1.3.2. Mechanism of Neurotoxicity and role of MAO inhibitors
In order to understand the mechanisms of neurotoxicity, the use of neurotoxic compounds has been introduced to elicit selective damage to a defined population of neurons.25 Deeper insight into the various mechanisms of neurodegeneration might pave the way to develop effective neuroprotective drugs. Selective injury can be induced in neurons by toxins, inactivating their neuronal transmitter by means of a membrane bound, high-affinity, energy- and sodium-dependent monoamine uptake (Figure 1.13). Toxins, the structural analogues of transmitters, can be taken up by the same reuptake mechanism. Endogenously produced neurotoxins have long been suspected of being involved in the pathogenesis of PD; however, convincing evidence supporting this concept still does not exist.26
Figure 1.13: Mechanism of Neurotoxicity
The discovery of the pethidine analogue 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP) has strengthened the neurotoxin hypothesis, because the pathology caused by MPTP is very similar to that observed in PD. MPTP is a pre-toxin, which destroys dopaminergic neurons in the substantia nigra pars compacta (SNpc),27 as well as damages other catecholaminergic neurons28 in non-human primates, with a similar regional distribution of neuronal loss to that of the human PD.29 MPTP is converted to 1-methyl-4-phenylpyridinium ion (MPP+) in the astroglia by MAO-B.30-31 MPP+ is released from astroglia and is selectively accumulated in catecholaminergic neurons by the DA transporter localised in the plasma membrane of the dopaminergic neurons.32 Inside the neurons MPP+ is taken up by the vesicular monoamine transporter33 and it causes a vesicular release of DA.34 Released DA undergoes autoxidation and produces ROS with the peroxidation of macromolecules leading to neuronal damage or death. MPP+ can inhibit NADH dehydrogenase by binding to mitochondrial respiratory complex I (Figure 1.14).35 Inhibition of complex I by MPP+ leads to the disturbance of mitochondrial energy production.36
Figure 1.14: Mechanism of MPTP Toxicity
It was discovered in 1985 that (-)-deprenyl could prevent the loss of cultured dopaminergic neurons caused by direct application of MPP+. This finding suggested that deprenyl possesses another mechanism of protection than the inhibition of the conversion of MPTP to MPP+, which is independent of MAO-B inhibition. The inhibitory potency of (-)-deprenyl on DA re-uptake may contribute to the protection against MPP+.37-39
It has been proved that (-)-deprenyl pre-treatment can protect neurons from all of these toxins. The neuroprotective effect of (-)-deprenyl against MPTP,27,40 DSP-4,41-42 5,6-dihydroxy-triptamine43 and AF64A44 was widely studied.11
Interest in selective inhibitors of monoamine oxidase B (MAO B, EC 22.214.171.124) has increased in the last years due to their therapeutic potential in aging related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). 1,2 Indeed, studies involving activity measurements of the two MAO isoforms, MAO A and MAO B, in postmortem brain have shown an age-related increase in MAO B but a constant activity of the isoenzyme A.45 Several pharmaceutical companies are currently working to design selective inhibitors of MAO-B. The structures of some of the compounds are under clinical phase studies.
Table 1.2: Some MAO inhibitors used and under development in the treatment of depression and of PD
Mode of action
A+B (brain selective)
Figure 1.16: Structures Some known inhibitors of MAO-A
Figure 1.15: Structures Some known inhibitors of MAO-B
Some of the Herbal Drugs with MAO inhibitory properties are listed below:
Selective MAO-A Inhibitors
Resveratrol (found in skin of red grapes)46
Selective MAO-B inhibitors
Catechin (found in the tea plant, cocoa, and cat's claw)
Desmethoxyyangonin (found in kava)
Epicatechin (also found in the tea plant, cocoa, and cat's claw)
Hydroxytyrosol (found in olive oil)
Piperine (found in pepper)
Nonselective MAO-A/MAO-B Inhibitors
Curcumin (found in turmeric)
Harmala alkaloids likeHarmine, Harmaline, Tetrahydroharmine, Harmalol, Harman, Norharman, etc(found in tobacco, syrian rue, passion flower, ayahausca, and Tribulus terrestris)
Rhodiola Rosea (active consituent(s) unknown)