Bio Transforming Enzymes

8/2/2019 Bio Transforming Enzymes

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Biotransforming Enzymes, Substrates and End Products

Biotransformation is the process within our body whereby a substance is changed, mainly

transformed, from one chemical to another by a chemical reaction. It is also known as

Metabolism or metabolic transformations.

Biotransformation is vital to survival in that it transforms absorbed nutrients (food, oxygen,

etc.) into substances required for normal body functions. For some pharmaceuticals, it is a

metabolite that is therapeutic and not the absorbed drug. Like, phenoxybenzamine, a drug given

to relieve hypertension, is biotransformed into a metabolite, which is the active agent. It also

serves as an important defense mechanism in those toxic xenobiotics and body wastes are

converted into less harmful substances and that can be excreted from the body.

Biotransforming Enzyme:

Chemical reactions are continually taking place in the body. Most of these chemical reactions

occur at significant rates only because specific proteins, known as enzymes, are present to

catalyze them, that is, accelerate the reaction.

These enzymatic reactions are not always simple biochemical reactions. Some enzymes require

the presence of cofactors or co-enzymes in addition to the substrate before their catalyticactivity can be exerted. Substrate is the substance that will be catalyzed. These co-factors exist

as a normal component in most cells and are frequently involved in common reactions to

convert nutrients into energy; Vitamins are an example of co-factors. It is the drug or chemical

transforming enzymes that hold the key to xenobiotic transformation. The relationship of

substrate, enzyme, co-enzyme, and transformed product is illustrated below:

Figure 01: Relationship of substrate, enzyme, co-enzyme, and transformed product

Most biotransforming enzymes are high molecular weight proteins, composed of chains of

amino acids linked together by peptide bonds. While an enzyme may encounter many different

chemicals, only those chemicals (substrates) that fit within the enzymes convoluted structure

and spatial arrangement will be locked on and affected. This is sometimes referred to as the

"lock and key" relationship. As shown in Figure 1, when a substrate fits into the enzyme's


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Figure 03: Metabolism of Procaine

Figure 05: Metabolism of Serotonin

The reactions catalyzed by xenobiotic biotransforming enzymes generally are divided into two

groups:

1. Phase I reactions Non-synthetic reactions

2. Phase II reactions Synthetic reactions

Phase I reaction: Phase I reactions are generally reactions which modify the chemical by adding

a functional structure. This allows the substance to "fit" into the Phase II enzyme so that it can

become conjugated (joined together) with another substance.

In Phase I reactions, a small polar group (containing both positive and negative charges) is

either exposed on the toxicant or added to the toxicant. The main Phase I reactions are:

- Oxidation,

- Reduction,

- Hydrolysis.

Table 01: Example of type of reaction and enzymes participate in phase I reaction

Reaction Enzyme

Procaine p-Aminobenzoic


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1. Oxidation: Oxidation is a chemical reaction in which a substrate loses electrons. There

are a number of reactions that can achieve the removal of electrons from the substrate. The

specific oxidizing reactions and oxidizing enzymes are numerous. Here are several of these

oxidation reactions.

Alcohol dehydrogenation

Aldehyde dehydrogenation

Alkyl/acyclic hydroxylation

Aromatic hydroxylation

Deamination

Desulfuration

N-dealkylation

N-hydroxylation

N-oxidation

O-dealkylation

Sulphoxidation


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Table 02: An overview of possible types of phase I biotransformation reaction (oxidations)

Oxidation of Drugs by Cytochrome P450: The cytochrome P450 superfamily (officiallyabbreviated as CYP) is a large and diverse group ofenzymes. The function of most CYP

enzymes is to catalyze the oxidation oforganic substances. The substrates of CYP enzymes

include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic

substances such as drugs and othertoxic chemicals. CYPs are the major enzymes involved in

drug metabolism and bioactivation, accounting for about 75% of the total number of different

metabolic reactions.

The most common reaction catalyzed by cytochromes P450 is a monooxygenase reaction, e.g.,

insertion of one atom of oxygen into an organic substrate (RH) while the other oxygen atom is

reduced to water:
http://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Catalysishttp://en.wikipedia.org/wiki/Redoxhttp://en.wikipedia.org/wiki/Organic_compoundhttp://en.wikipedia.org/wiki/Enzyme_substratehttp://en.wikipedia.org/wiki/Metabolismhttp://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Steroidhttp://en.wikipedia.org/wiki/Xenobiotichttp://en.wikipedia.org/wiki/Toxichttp://en.wikipedia.org/wiki/Drug_metabolismhttp://en.wikipedia.org/wiki/Monooxygenasehttp://en.wikipedia.org/wiki/Redoxhttp://en.wikipedia.org/wiki/Enzymehttp://en.wikipedia.org/wiki/Catalysishttp://en.wikipedia.org/wiki/Redoxhttp://en.wikipedia.org/wiki/Organic_compoundhttp://en.wikipedia.org/wiki/Enzyme_substratehttp://en.wikipedia.org/wiki/Metabolismhttp://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Steroidhttp://en.wikipedia.org/wiki/Xenobiotichttp://en.wikipedia.org/wiki/Toxichttp://en.wikipedia.org/wiki/Drug_metabolismhttp://en.wikipedia.org/wiki/Monooxygenasehttp://en.wikipedia.org/wiki/Redox


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RH + O2 + 2H+ + 2e ROH + H2O

Aliphatic Oxidation:

Aromatic Hydroxylation:

N-Dealkylation:


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N-Hydroxylation:

Desulfuration:

2. Reduction: Reduction is a chemical reaction in which the substrate gains electrons.

Reductions are most likely to occur with xenobiotics in which oxygen content is low. There

are fewer specific reduction reactions than oxidizing reactions. Here are several of these

reduction reactions.

Azo reduction

Dehalogenation

Disulfide reduction

Nitro reduction

N-oxide reduction

Sulfoxide reduction

Table 03: An overview of possible types of phase I biotransformation reaction (reductions)


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Azo Reduction:

Nitro Reduction:

Dehalogenation: There are three major mechanisms of dehalogenation:

i. Reductive dehalogenation: Halogen replaced with a hydrogen atom.

ii. Oxidative dehalogenation: Halogen & hydrogen replaced with oxygen

iii. Double dehalogenation: 2 halogens replaced from two adjacent Cs to form a C-Cdouble bond

3. Hydrolysis: Hydrolysis is a chemical reaction in which the addition of water splits the

toxicant into two fragments or smaller molecules. The hydroxyl group (OH-) is

incorporated into one fragment and the hydrogen atom is incorporated into the other. Larger

chemicals such as esters, amines, hydrazines, and carbamates are generally biotransformed

by hydrolysis.

Table 04: An overview of possible types of phase I biotransformation reaction (Hydrolysis)


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Ester Hydrolysis:

Epoxide Hydrolase:

Phase II reaction: Phase II reactions consist of those enzymatic reactions that conjugate the

modified xenobiotic with another substance. A xenobiotic that has undergone a Phase I reaction

is now a new intermediate metabolite that contains a reactive chemical group, e.g., hydroxyl (-

OH), amino (-NH2), and carboxyl (-COOH). Many of these intermediate metabolites do not

possess sufficient hydrophilicity to permit elimination from the body. These metabolites must

undergo additional biotransformation as a Phase II reaction.

Phase II reactions are conjugation reactions, that is, a molecule normally present in the body is

added to the reactive site of the Phase I metabolite. The result is a conjugated metabolite that is

more water-soluble than the original xenobiotic or Phase I metabolite. Usually the Phase II


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metabolite is quite hydrophilic and can be readily eliminated from the body. The primary Phase

II reactions are:

Glucuronide conjugation - most

important reaction

Sulfate conjugation - important

reaction

Acetylation

Amino acid conjugation

Glutathione conjugation

Methylation

Table 01: Example of type of reaction and enzymes participate in phase I reaction

Reaction Enzyme

Methylation S-Methyltransferases

O- Methyltransferases

N- Methyltransferases

Acetylation N-Acetyltransferases

Acetyltransferases

Glucuronide conjugation Glucuronosyltransferases

Glutathione conjugation Glutathione S-transferase

Glucuronide conjugation:

Amino acid conjugation:


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Methylation:

Acetylation:

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Bio Transforming Enzymes