Running head: BIOCHEMISTRY ASSIGNMENT 1

Student’s Name

Student’s Number

Institutional Affiliation
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Biochemistry Assignment

A.

CYP enzymes are usually regarded as the main enzymes family with the capacity of
catalyzing oxidative transformation of most medications, the psychotropic drugs being one of
them. CYP enzymes are bound to membranes within a cell and constitute a heme pigment which
absorbs light at a wave length of 450nm when exposed to carbon monoxide. Moreover, the
metabolism of CYP enzyme is a significant source of variability in drug pharmacokinetics and
the response of patients to treatments. With a n estimated number of CYPs which are functional
in humans only 12 enzymes play the role of biotransformation of commonly used drugs and
foreign substances. CYPs are mainly expressed in the liver, though they also occur in reduced
amounts in the small intestine, placenta, kidneys and lungs. The main CYP phase 1 metabolic
pathways include the cytochrome enzymes catalyze oxidation and reduction which has the ability
to increase activities and may transform the substrate from an inactive to an active form. The
CYP2D6 enzyme which is a member of the CYP enzymes family performs a significant
responsibility in the metabolism of more than 70 drugs which belong to the classes of
antipsychotics, antidepressants, antiarthemics, mood stabilizers and beta blockers antiemetic’s.
the CYP2D6 enzyme polymorphism is responsible for the variations which are observed in drug
responses among different kind of patients. The first class of patients in which the metabolism
induve various variations are the patients with genetic variability. Genetic variability in these
enzymes may induce a patient response to the commonly prescribed drugs, including
antidepressants, beta blockers and antipsychotics. As a result of considerable genetic variability
of the CYP2D6 enzyme, the drugs that are metabolized with CYP2D6, several individuals will
do away with these drugs quickly (ultra-rapid metabolizers) while others will eliminate the drug
too slowly (poor metabolizers). If a medication is broken down at a faster rate, the efficacy of the
particular drug may be reduced. On the other hand if the drug is broken down slowly, toxicity
may occur. Thus, the drug dose may have to be altered a little bit to counter attack the rate at
which it is metabolized by CYP2D6.
As well as in the liver, CYP2D6 is also expressed in the brain where it is responsible in
the metabolism of endogenous substances and neurotransmitters including dopamine.
Neuroleptic malignant syndrome has been researched within the Japanese population and has
been associated with CYP2D6.
Drug interactions involving CYP2D6 Enzyme

Risperidone belongs to a class of second-generation antipsychotics that is metabolized

mostly by CYP2D6. Because risperidone is metabolized through the cytochrome P450 (CYP)
2D6 mitochondrial pathway, ethnic variations and interactions with medications that inhibit or
stimulate this system will impact risperidone plasma concentrations. Inhibitors of the CYP2D6
enzyme, such as paroxetine, fluoxetine, and quinidine, as well as inducers of the 2D6 enzyme,
such as carbamazepine, phenytoin, rifampin, and phenobarbital, can influence the metabolism of
risperidone. Inhibitors of the 2D6 enzyme raise risperidone levels in the bloodstream and slow
the conversion to 9-OH-risperidone. Fluoxetine and paroxetine (both powerful 2D6 inhibitors)
increased risperidone plasma levels by 2.5 and 3.9 times, respectively. The use of risperidone, a
mild inhibitor of CYP 2D6, in combination with clozapine may result in higher clozapine serum
concentrations.
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CYP 2D6 is the enzyme that breaks down first-generation antipsychotics such
haloperidol, perphenazine, thioridazine, and chlorpromazine. Because SSRIs, particularly
fluoxetine and paroxetin, are powerful inhibitors of the CYP 2D6 enzyme, co-administration of
these medications with first-generation antipsychotics metabolized by CYP 2D6 will raise
antipsychotic serum levels. This could lead to an increase in extrapyramidal side effects (EPS)
worsening. Other CYP 2D6 substrates, such as heterocyclic antidepressants, beta-blockers, and
cimetidine, may raise antipsychotic plasma concentrations when used with first-generation
antipsychotics (Ayano, 2016).
The CYP 2D6 isozyme is inhibited by selective serotonin reuptake inhibitors (SSRIs) as
Fluoxetine, paroxetine, sertraline, and citalopram. Coadministration of a selective serotonin
reuptake inhibitor (SSRI) with other CYP 2D6 substrates increases serum concentrations of other
medications, such as beta-blockers like labetalol (Normodyne), metoprolol, propranolol, and
timolol, and type 1C antiarrhythmics like encainide (Enkaid), flecainide (Tambocor),
propafenone (R Fluoxetine is a strong CYP 2D6 inhibitor, and combining ypoglycem with
insulin or an oral ypoglycemic can cause hypoglycemia in diabetic people. On the other hand,
Propranolol, metoprolol, timolol, and alperolol are some of the most commonly used beta
blockers that are metabolized largely by CYP2D6. Beta blockers, such as propranolol, timolol,
labetalol, and (Normodyne), metoprolol, increase in serum concentrations when used with
antidepressants (substrates of CYP 2D6) such as selective serotonin reuptake inhibitors (SSRI).
Interactions between CYP2D6 enzymes are based on either enzyme stimulation or
inhibition. Drugs that stimulate the production of CYP2D6 enzymes increase the amount of an
enzyme that metabolizes psychotropic drugs. This limits the amount of psychotropic drugs
available, potentially reducing their effectiveness. The synthesis of enzymes needed to digest
psychotrophic medicines is reduced by drugs that block CYP2D6 enzymes. This raises the
amount of psychotropic medicines in the body, perhaps resulting in an overdose or hazardous
effects. Furthermore, some medicines may serve as inhibitors or inducers of CYP2D6 enzyme
expression, resulting in decreased or increased CYP2D6 activity, respectively. When such a
medicine is taken with a second drug that is a CYP2D6 substrate, the first drug may impact the
second drug's clearance rate through a drug-drug interaction. Understanding the medicines
metabolized by CYP2D6 (substrates), inducers, and inhibitors is critical for proper drug selection
and potential effects. Furthermore, it is critical to choose prescriptions that are more beneficial
for patients, particularly when many medications are being used at the same time.
B.

Chemical Degradation of Major Neurotransmitters

Dopamine is a neurotransmitter involved in the control of movement and the loss of

dopaminergic neurons in the nigrostriatal systems that contain neuromelanin. Dopamine is also
implicated in the development of motor symptoms in Parkinson's disease patients. The cytosolic
enzymes tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC) catalyze
the hydroxylation of the amino acid tyrosine to L-dihydroxyphenylanaline (L-dopa) and the
decarboxylation of L-dopa to dopamine, respectively, in a sequential reaction. Once dopamine is
inside monoaminergic synaptic vesicles, which have a low pH, these protons are securely linked
to the hydroxyl group (Kimmel et al., 2001). A vesicular monoaminergic transporter-2 (VMAT-
2) is found on the membrane of monoaminergic synaptic vesicles and catalyzes the uptake of
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dopamine into these vesicles. An ATPase in these monoaminergic synaptic vesicles hydrolyzes
ATP to ADP and Pi, and one proton (H+) is translocated into the vesicle, resulting in a proton
gradient. This proton gradient is used by VMAT-2 to take in one molecule of dopamine while
simultaneously releasing two protons.
Without metal-ion catalysis, dopamine in the cytosol spontaneously oxidizes to
aminochrome . As a result, VMAT-2 plays a critical function in avoiding dopamine oxidation in
dopaminergic neurons. Monoamino oxidase (MAO) and catechol ortho-methyl transferase are
two more enzymes that prohibit dopamine from being converted to aminochrome (COMT).
MAO catalyzes the oxidative deamination of dopamine's amino group to 3,4-
dihydroxyphenylacetaldehyde, which results in the creation of an ammonium molecule and
hydrogen peroxide in the cytosol. Aldehyde dehydrogenase can then convert 3,4
dihydroxyphenylacetaldehyde to 3,4-dihydroxyphenylacetic acid (DOPAC), which can
subsequently be catalyzed by COMT and transformed to homovanillic acid. COMT can also
methylate dopamine, resulting in 3-methoxytyramine, which the enzyme MAO can convert to 3-
methoxy-4-hydroxyphenylacetaldehyde, hydrogen peroxide, and NH3. Finally, 3-methoxy-4
hydroxyphenylacetaldehyde is converted to homovanillic acid by the enzyme aldehyde
dehydrogenase. On neurons, glial cells, and other cell types, MAO enzymes are found in the
outer membranes of mitochondria.
MAO-A is mostly present in catecholaminergic neurons, whereas MAO-B is found in
serotonergic, histaminergic, and astrocyte neurons. COMT is divided into two isoforms: soluble
(S-COMT) and membrane-bound (MB-COMT). Microglia, astrocytes, and certain neuronal
cells, such as pyramidal neurons, cerebellar Purkinje and granular cells, and striatal spiny
neurons, all contain both isoforms [9]. Even in the presence of VMAT-2, MAO-A, and S-
COMT, which prevent the availability of free dopamine in the cytosol, dopamine oxidizes to
aminochrome.
Protons in free cytosolic dopamine separate from their hydroxyl groups, facilitating the
oxidation of dopamine to dopamine o-quinone. This oxidation can start with a one-electron
oxidation of dopamine to create a dopamine o-semiquinone radical (reaction 1), which is then
oxidized to dopamine o-quinone (reaction 2) by reducing two oxygen molecules to superoxide
radicals. During a one-electron reduction of aminochrome, the dopamine o-semiquinone radical
does not strongly react with oxygen, resulting in the creation of leukoaminochrome o-
semiquinone radical. Two dopamine o-semiquinone radicals can then disproportionate, resulting
in one molecule of dopamine o-quinone and one molecule of dopamine (reaction 3). The enzyme
tyrosinase catalyzes the two-electron oxidation of dopamine to dopamine o-quinone. Electron
spin resonance does not detect the presence of dopamine o-semiquinone. At physiological pH,
dopamine o-quinone is unstable in the cytosol, and its amino chain cyclizes (reaction 5),
resulting in aminochrome.
On the other hand, Norepinephrine is made from the amino acid tyrosine and stored in
synaptic vesicles. It works by being released into the synaptic cleft, where it activates on
adrenergic receptors, and then signaling is terminated either by norepinephrine breakdown or
absorbed by neighboring cells. The amino acid tyrosine is converted to norepinephrine by a
number of enzymatic processes in the adrenal medulla: The oxidation of tyrosine to
dihydroxyphenylalanine (L-DOPA) (DOPA = 3,4-DiHydroxy-L-Phenylalanine) is the initial
process, which is catalyzed by tyrosine hydroxylase. This is the step where the rate is limited.
The neurotransmitter dopamine is then decarboxylated, which is mediated by pyridoxal
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phosphate and DOPA decarboxylase. Dopamine beta hydroxylase is responsible for the final
-oxidation into norepinephrine, which requires ascorbate as a cofactor (electron donor).
The enzyme choline acetyltransferase produces acetylcholine from acetyl coenzyme A
and choline. This enzyme is assumed to be found largely in the cytoplasm of nerve terminals in
the nervous system. Coenzyme A is generated in mitochondria and then transported over the
mitochondrial membrane into the cytoplasm, where it binds to choline acetyltransferase. Choline
used in acetylcholine generation is taken from dietary sources in addition to its synthesis in the
liver. Choline, in both its free and phospholipid forms, is transported into the brain by a carrier
system found in capillary endothelial cells. When choline-containing phospholipids are
hydrolyzed, choline that is used in acetylcholine production is liberated. Because amounts of
acetyl coenzyme A and choline predicted to be present in the nerve terminal do not saturate
choline acetyltransferase, it appears that the rate of acetylcholine production is reliant on
precursor availability. Product inhibition regulates enzyme activity; acetylcholine inhibits
choline acetyltransferase by interacting to an allosteric site on the enzyme. Furthermore, the rate
of acetylcholine synthesis is influenced by mass action and neuronal activity. Phosphorylation
generated by protein kinases helps to regulate enzyme activity in the short term. There are no
extremely specific and powerful inhibitors of the enzyme, and it should be emphasized that
blocking this phase in the acetylcholine life-cycle (e.g. with naphthylvinylpyridine) has a less
dramatic effect on the transmitter than blocking choline transport. Acetylcholine is released from
vesicles and attaches to post-synaptic receptors before being broken down by
acetylcholinesterase. Anticholinesterases, on the other hand, attach to the enzyme and prevent
the neurotransmitter from being broken down. Acetylcholine keeps activating the receptor.
Anticholinesterases (anti-AChE) are a class of compounds that can replace ACh at the active site
of AChE, lowering the neurotransmitter's ability to connect to AChE and effectively limiting the
pace at which ACh is broken down. The presence of AChE inhibitors results in an excess build-
up of ACh at the synapse because there is no presynaptic re-uptake mechanism to transport ACh
back into the presynaptic cell and because ACh cannot quickly dissolve into the surrounding
media. This build-up causes an increase in ACh activity at post-synaptic receptor molecules,
resulting in continuous action potential firing.
Likewise, Tryptophan hydroxylase transforms the amino acid tryptophan to 5-
hydroxytryptophan, which is then decarboxylated to generate 5-hydroxytryptamine, which is
then converted to serotonin (serotonin). Monoamine oxidase converts serotonin to the inert
amino acid of the same name (Fig. 33.8). Once generated, serotonin can be stored in vesicles at
nerve endings; it is inactivated in a similar way as catecholamines, primarily through reuptake.
The genetic underpinnings, transcriptional regulation, substrate choice, inhibitor affinity, and
regional distribution of two MAO isoenzymes, A and B, have been found. Despite the fact that
MAO A has the highest selectivity for 5-HT and catalyzes its metabolism under physiological
settings, MAO B is the sole isoenzyme found in 5-HTergic neurons. This chapter examines the
evidence for MAOs' biochemistry, genetics, and neurobiology in relation to their roles in the
regulation of 5-HTergic neurotransmission as determined by investigations on the effects of
pharmacological and genetic inactivation (Blows, 2000).
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References

Blows, W. T. (2000). Pharmacology update: Neurotransmitters of the brain: Serotonin

noradrenaline (Norepinephrine), and dopamine. Journal of Neuroscience Nursing, 32(4),

234.

Kimmel, H. L., Joyce, A. R., Carroll, F. I., & Kuhar, M. J. (2001). Dopamine D1 and D2

receptors influence dopamine transporter synthesis and degradation in the rat. Journal of

Pharmacology and Experimental Therapeutics, 298(1), 129-140.

Ayano, G. (2016). Psychotropic medications metabolized by cytochromes P450 (CYP1A2)

enzyme and relevant drug interactions: Review of articles. Austin Journal of

Pharmacology and Therapeutics, 4(2), 2-5.