microbial bio-transformation

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microbial biotransformation chapter in medicinal chemistry


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Definition: It is a conversion of substrate into product by using micro organism . Types of cells in conversion: Plant cells Animal cells Microbial cells Introduction:-

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HISTORY: The first microbial conversion was formation of ethanol from cane sugar Mamoli and Vercellone in 1937 Microbial transformation of steroids

Characteristics (advantages over chemical reaction):

a) Regiospecificity : The substrate molecule is usually attack to the same site even if several groups of equivalent or similar reactivity are present. Characteristics (advantages over chemical reaction) CH2OH CH2OH OH H O ACETOBACTOR SOBAXYDANS D-SORBITOL L-SORBOSE

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b) Reaction specificity:- The catalytic activity is restricted to a single reaction type. It means this side reaction are not expected as long as the one enzyme is involved in a particular biotransformation. Specific organism must be use carry out specific type of biotransformation. e.g.:- Bacteria and yeast are particularly active in oxido -reductive reaction where as the fungi are specialist of hydroxylation.

c) Steriospecificity:- :

If a enzyme reaction produces a new asymmetric centre, usually only one of the possible enantiomer is form resulting in to optically pure compound. It can easily make a differentiation between enantiomers of recemic mixture. E.g.:-Ophiobolus herpotrichus has been used in the separation of D&L-21-deoxy - 18dehydro aldosterone. The D-18-dehydro aldosterone while the L-isomer remains unchanged. c) Steriospecificity:-

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DL-21-Deoxy aldosterone D-18-Dehydro aldosterone L-21-Deoxy aldosterone

d) Mild reaction condition:- :

Activation energy of chemical reaction is greatly lowered by interaction of substrate and enzyme. This biotransformation takes place under mild condition such as pH near neutrality, room temperature & at normal pressure. So even a labile compound can be converted without undesired decomposition or isomerization. e)High yieald f)Complex molecules synthesis g)Lesser steps d) Mild reaction condition:-

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Disadvantages:- Enzyme exhibit low or no activity in most organic solvents and gets denatured both at high temperature and under strongly acidic or basic condition. The enzyme subjected to product and substrate inhibition so reaction may have to be performed at low substrate or product concentration.

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A. REQUIRMENT a. Presence of enzyme or enzymes catalyzing the desired transformation b. The absence the suppression of activity of enzymes catalyzing further conversion of product. C.PH , Temperature,Aerobic and anaerobic condition,Cell membrane. A B C :- Practical aspect of microbial transformation:-

B) Selection of organism:-:

Selection of organism is depends on following parameter- Micro organism should able to give desire product. The culturing of micro organism should be economical. The reaction must be complete at a given period of time. Micro organism should not produce by products B) Selection of organism:-

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There are 5 basic techniques for selection Of organism:- Random screening Parallel system Interference with normal metabolism Enrichment technique Mixed culture.

  1. Random screening:- :

The substrate is added to a large number of micro-organisms and after a given time the medium is analyzed for the presence of product . 1. Random screening:- This technique is described for the screening of large number of fungi for the ability of their spores to carry out a given steroid conversion. The spores are spotted with the substrate on a glucose-treated TLC Plate and after incubation the chromatogram can be developed.

2. Parallel system:- :

A suitable organism is obtained by literature survey for similar conversion and testing the organism or closely related once in the system under study. 2. Parallel system:-

3 .Interference with normal metabolism:- :

This method has been successful in a number of cases starts with the selection of organism that are able to transform the substrate in to some product via the required substance. The organism is then changed by mutation or alternatively the conversion of the required substance is inhibited. 3 .Interference with normal metabolism:-

4. Enrichment technique:- :

The large amount of substrate is added to soil samples together with water and additional nutrients. The mixture is set aside for a period of time to allow proliferation of those organism that are capable of utilizing this substrate. This sample subsequently is investigated for strains that have the desired properties. E.g.: when a piece of paper is buried in soil, within a weak it will be covered by billions of individuals of the genus cytophaga. 4. Enrichment technique:-

5. Mixed culture:- :

It may be advantageous to use a mixture of two or more micro-organisms for the conversion of particular substrate. The development of such fermentation is usually too difficult to allow a practical application. E.g.: the transformation of tropane in to pseudotropane is accomplished by the combined action of Bacillus alvei & enterococcus, but not each of these bacteria separately. 5. Mixed culture:-

C) Large scale conversion:- :

11 alpha-Hydroxylation: the introduction of the hydroxyl group at the 11 alpha- position of progesterone, by an enzyme hydroxylase used in the synthesis of hydrocortisone. C) Large scale conversion:-


A . Conversion of uncommon substrate:- Energy is needed to carried out the conversion. This energy originates from reserve materials present in the cell or from medium components. The ability to convert certain substances may be due to the presence of an enzyme that normally functions by catalyzing the conversion of structurally related substances. SOME THEROTICAL ASPECTS OF MICROBIAL TRANSFORMATION:-

B. Interference with metabolic pathway:- :

The degradation of the organic compounds in the medium, catabolism is usually oxidative. The catabolic conversion serves to provide the cell both with energy and with compounds needed for the biosynthesis of all cell constituents. Such compounds are intermediates in the degradation pathway and may be degraded further. The right balance between the biosynthesis and degradation is kept by way of regulation mechanisms. B. Interference with metabolic pathway:-

Conversion by micro-organism:- :

The conversion are arranges according to the type of reaction. Oxidation. Reduction. Esterification. Glycosylation. Hydrolysis. Addition. Amination. Deamination. Dehydration. Conversion by micro-organism:-

1.Oxidation:- :

A. Hydroxylation:- Cumic acid is hydroxylated to 3-hydroxycumic acid by pseudomonas strain. 1.Oxidation:-

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B. Epoxidation This type of conversion is almost exclusively found with steroids. Micro-organisms that are able to accomplish an axial hydroxylation are also through to have the ability to epoxidize a double bond at the same carbon atom.

  C. Oxidation of carboxylic acid: :

Citral is oxidized to geranic acid by several pseudomonas strain C. Oxidation of carboxylic acid:

D. Oxidation of ketone to ester: :

Camphor is converted in to 1, 2-campholide by a pseudomonas strain. D. Oxidation of ketone to ester:

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E. Oxidative degradation: The conversion of naphthalene into salicylic acid bacterium.

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E. Formation of double bond by dehydration : Cholesterol is converted into 7-dehydrocholesterol by Azotobacter species. Cholesterol 7-dehydrocholesterol

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2. Reduction: A. Reduction of ketone Reduction of 17-keto group of steroid by yeast.

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B. Reduction of Halogen: removal of bromine from 14-odienone by trametes sanguinea results in formation of a double bond. 14-odienone

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3. Reduction of double bond:- Conversion of 6-dehydrotestosterone into Testosterone by Nocardia restrictus. 6-dehydrotestosterone Testosterone

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3) Esterification: 1. Carboxylation: the most common esterification is acetylation. E.g.: acylation of chloramphenicol by streptomyces coelicolor chloramphenicol

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2. N- Acylation : e.g._- streptomyces roseochromogenes will convert a 21-aminosteroid into the aminoacyl derivative 21-aminosteroid aminoacyl derivative

4) Glycosylation : Hypoxanthone is glycosylated to inosine by corynebacterium species :

4) Glycosylation : Hypoxanthone is glycosylated to inosine by corynebacterium species Hypoxanthone inosine

5)Hydrolysis: Acetates may also be hydrolyzed by yeast & Nocardia corallina   :

5)Hydrolysis: Acetates may also be hydrolyzed by yeast & Nocardia corallina 6) Addition: Addition of water oleic acid leads to 10-hydroxystearic acid. oleic acid 10-hydroxystearic acid.

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7) Amination: Transformation of dihydroxyphenylpyruvic acid in to L-dopa can be performed by several micro-organisms. 8) Deamination: guanine is converted to xanthine by E.coli strains guanine xanthine dihydroxyphenylpyruvic acid L-dopa

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9) Dehydration: The conversion of cis-terpin hydrates into alfa-terpineol by brevibacterium strain. Cis terpin alfa-terpineol


1 PHARMACEUTICAL MICRBIOLOGY by N.K.JAIN 2 PHARMACEUTICAL BIOTECHNOLOGY by K.Sambamurthy and Ashutosh Kar 3. www.google.com 4.Drug Design by Dr.V M Kulkarni REFERENCES

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