Physostigmine Biosynthesis

Biosynthesis:

-Unusual acetylation-dependant reactions

-Gene clusters

-Enzymes involved

-Follow up

Conclusion:

we have identified and dissected the seven enzymes and eight reaction steps involved in the biosynthesis of the pyrroloindole drug physostigmine from 5-hydroxytryptophan. Initial decarboxylation of 2, followed by acetylation of the amine, results in the well-known intermediate normelatonin, which is modified at the C5 hydroxy group by carbamylation and methylation.

Report On

Synthesis:

Physostigmine Biosynthesis

Physostigmine

is produced during the aerobic fermentation of suitable aqueous media under conditions described here inafter by strains of Streptomyces griseofuscus

Such media contain sources of carbon and nitrogen assimilable by the microorganisms. In general, carbohydrates such as sugars, for example, glucose, sucrose, maltose, mannose, rhammose and the like, grains such as coats, rye, wheat, corn and the like and starches are suitable sources of assimilable carbon in the nutrient media. it is usually found that the amount of carbohydrate between about 1 and 6% by weight of the medium is satisfactory. These carbon sources can be used individually or several such carbon sources may be combined in the medium.Various nitrogen sources such as yeast hydrolysates, yeast autolysates, soybean meal, casein hydrolysates, corn steep liquors, distiller’s solubles, meat extract and the like are readily assimilable by the new strain of Streptomyces griseofuscus in the production of physostigmine. The various sources of nitrogen can be used alone or in combination in amounts ranging from 0.2 to about 6% by weight of the medium

Production of physostigmine:-

a novel process for preparing the compound physostigmine by the fermentation of nutrient media with suitable strains of a microorganism.

The fermentation process provides a more convenient method for obtaining physostigmine since the process is independent of the conventional slow growing plant source.

As such this new process offers greater control over the size of the yield. The new process for preparing physostigmine comprises cultivating, under controlled conditions,

a proviously known strain of microorganism which has been named Streptomyces griseofuscus in an aqueous nutrient medium under aerobic conditions. The microorganism was isolated from a sample of soil from Orense', Spain.

Julian's synthesis of physostigmine

The following are examples of media suitable for growing Streptomyces griseofuscus and producing physostigmine.

Examples of medium :

MEDIUM NO:1

Fermentation 1 Meat extract g__ 3.0

Casein hydrolysate (NZ amine, type B) ____ __g__ 10.0

Glucose g 15.0

Ardamine (yeast autolysate) _____________ __g__ 1.0

NaCl g__. 2.5

CaCOa __ g 5.0

Distilled H2O ____ ml 1000

pH adjusted to 7.2 with NaOH.

Pharmacological action

1)Physostigmine acts by interfering with the metabolism of acetylcholine. It is a reversibl inhibitor of acetylcholinesterase enzyme.

2) It indirectly stimulates both nicotinic and muscarinic acetylcholine receptors

Uses:

1-glaucoma and

2-delayed gastric emptying

3- Because it prolongs the effect of endogenous acetylcholine, physostigmine can be used as an antidote to anticholinergicoisons such as hyoscyamine/atropine , and it also reverses the effects of competitive muscle relaxants such as curare, tubocurarine, atracurium

4- Acetylcholinesterase-inhibiting drugs are also of value in the treatment of Alzheimer’s disease, which is characterized by a dramatic decrease in functionality of the central cholinergic system.

Use of acetylcholinesterase inhibitors can result in significant memory enhancement in patients, and analogues of physostigmine are

presently in use (e.g. rivastigmine) or have been tested in clinical trials (e.g. phenserine )These analogues have

a longer duration of action, less toxicity, and better bioavailability than physostigmine.

Side Effects:

1-nausea, 2-vomiting 3-diarrhea,

4-anorexia 5-dizziness 6-headache,

7-stomach pain 8-sweating 9-dyspepsia

10- seizures.

The carbamate functional group readily hydrolyses in water, and in bodily conditions. The metabolite thus formed from physostigmine and some other alkaloids (e.g. cymserine) is eseroline,

which research has suggested may be neurotoxic to humans. Death can result from failure of the respiratory system and paralysis of the heart.

An overdose can cause cholinergic syndrome.

under supervision of

Pharmacognosy Department

Physostigmine

Origin:-

Is the seed of a leguminous plant Physostigma venenosum (the Calabar bean or ordeal bean) a native of tropical Africa,

poisonous to humans

Overview

1- Introduction

- Biosynthesis in general

2-Physostigmine in details

-Origin

-Nature

-Pharmacology

-Uses

-Side effects

3-Synthesis of physostigmine

4-Biosynthesis of physostigmine

-Unusual acetylation-dependant reactions

-Gene clusters

-Enzymes involved

-Follow up

5-Tissue culture

6-Conclusion

7-Refrences

Biosynthesis Def. & Overview

Living plants considered as biosynthetic laboratory

The formation of chemical compounds by a living organism.

The laboratory preparation of biological molecules by the use of reagents or catalysts derived from natural substances and modeled on a series of reactions occurring in a living organism.