Acetate Pathways

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Accordingg to B Pharm V sem PCI syllabus of Pharmacognosy and Phytochemistry II.Following presentation includes the detailed study of Acetate pathways

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ACETATE PATHWAYS:

ACETATE PATHWAYS By Dr. Nitu Singh Associate Professor Oriental College of Pharmacy and Research

Acetate pathway:

Acetate pathway Acetate occupies central position in relation to various metabolic pathways. They utilized for the formation of Straight chain compounds Aromatic Compounds

Types of Acetate Pathway:

Types of Acetate Pathway Two main roots of Acetate Pathway Acetate Melonate Pathway = Synthesize Fatty acids and Polyketides Mevalonic Acid Pathway / Isoprenoid Pathway =Synthesize Terpenes and Steroids

Slide 4:

Acetate Melonate Pathway : In this Malonyl CoA is synthesized .Various acetyl group attached to Malonyl CoA and forms fatty acids and then Lipids (Sec. Metabolites) are synthesized Mevalonic Acid Pathway :In this Mevalonic Acid is synthesized which then forms Isoprenoids through series of chemical reactions and then terpenoids (Sec. Metabolites) are synthesized.Isoprenoids are the starting material of steroid synthesis

Acetate Melonate Pathway:

Acetate Melonate Pathway The main products of this pathway are the fatty acids and polyketides . Acetyl coenzyme A (l), the precursor of this pathway, undergoes carboxylation with carbon dioxide to produce malonyl coenzyme A (2) with a more reactive methylene group. This can then react with a second molecule of acetyl coenzyme A and then decarboxylate to form a four carbon chain, acetoacetyl coenzyme A (3).

Slide 8:

The latter can further react with another malonyl unit in a similar way to provide further linear extension of the polyketide chain which may then cyclise via two major routes, path ’ a and ' b*, to yield two types of phenol derivatives, viz., the acylphloroglucinols (4 ) and the orsellinic acids ( 5 )

Slide 9:

Resorcinol (6) and salicyclic acid (7) derivatives would be obtained if reduction of an uninvolved ketone occurred prior to cyclisation. In all probability, the polyketide chain being highly reactive would remain enzyme bound throughout its formation and subsequent cyclisation. Alternatively, acetyl CoA gives rise to the aliphatic amino acids, like ornithine and lysine via the tricarboxylic acid cycle

Mevalonic Acid Pathway:

Mevalonic Acid Pathway Biosynthesis of active building block (C5 Units) The  mevalonate pathway, also known as the  isoprenoid pathway or HMG- CoA reductase pathway, is an essential metabolic pathway present in eukaryotes,  archaea , and some bacteria.

Slide 11:

The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylally pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 bimolecular such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

Slide 13:

Terpenoids and steroids are biosynthesised by the acetate - mevalonate pathway. The biogenesis of these compounds follows the 'Isoprene Buie * according to which they are built up from isoprene units joined by a head to tail linkages The primary precursor is mevalonic acid , which in turn is derived from acetyl CoA through the intermediate formation of acetoacetyl CoA and 3-hydroxy-3~methyl-glutaryl CoA .

Mevalonate Pathway :Step by Step:

Mevalonate Pathway :Step by Step Acetyl- CoA  (citric acid cycle) undergoes condensation with another acetyl- CoA molecule to form acetoacetyl-CoA in the presence Of enzyme Acetoacetyl-CoA thiolase Acetoacetyl-CoA condenses with another Acetyl- CoA molecule to form 3- h ydroxy-3- m ethyl g lutaryl-CoA (HMG- CoA ) in the presence of enzyme HMG- CoA synthase

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HMG- CoA is reduced to  mevalonate  by NADPH by HMG- CoA reductase enzyme This is the rate limiting step in cholesterol synthesis, which is why this enzyme is a good target for pharmaceuticals ( statins ) Mevalonate is phosphorylated at the 5-OH position to yield mevalonate-5-phosphate (also called  phosphomevalonic acid )  by enzyme mevalonate-5-kinase

Slide 17:

Mevalonate is phosphorylated at the 3-OH position to yield mevalonate-3-phosphate by enzyme mevalonate-3-kinase. 1 ATP is consumed. Mevalonate-3-phosphate is phosphorylated at the 5-OH position to yield mevalonate-5-phosphate  (also called  phosphomevalonic acid ) by enzyme mevalonate-3-phosphate-5-kinase. 1 ATP is consumed

Slide 18:

mevalonate-5-phosphate is phosphorylated to yield mevalonate-5-pyrophosphate by enzyme phosphomevalonate kinase . 1 ATP is consumed. Mevalonate-5-pyrophosphate is decarboxylated to yield isopentenyl pyrophosphate (IPP) by enzyme mevalonate-5-pyrophosphate decarboxylase . 1 ATP is consumed. Isopentenylpyrophosphate  is  isomerized  to  dimethylallyl pyrophosphate by Enzyme isopentenyl pyrophosphate isomerase

Slide 19:

The mevalonate pathway begins with acetyl- CoA  and ends with the production of IPP and DMAPP. It is best known as the target of  statins , a class of cholesterol lowering drugs. Statins inhibit HMG- CoA reductase  within the mevalonate pathway.

Slide 21:

The six-carbon compound MVA is transformed into the five-carbon phosphorylated isoprene units in a series of reactions, beginning with phosphorylation of the primary alcohol group. Two different ATP-dependent enzymes are involved, resulting in mevalonic acid diphosphate,and decarboxylation/dehydration then follow to give IPP (isopentyl pyrophoshphate).

Slide 22:

IPP is isomerized to the other isoprene unit, DMAPP (3,3-dimethyl allyl pyrophosphate), by an isomerase enzyme. This conversion generates a reactive electrophile and therefore a good alkylating agent. DMAPP possesses a good leaving group, the diphosphate.

Slide 23:

These two main intermediates IPP and DMAPP set the ‘active isoprene’ unit as a basic building block of isoprenoid compounds. Both of these units yield geranyl pyrophosphate (C10- monoterpenes ) which further on association with IPP produces farnesyl pyrophosphate (C15- sesquiterpenes ).

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Farnesyl pyrophosphate with one more unit of IPP develops into geranylgeranyl pyrophosphate (C20- diterpenes). The farnesyl pyrophosphate multiplies with its own unit to produce squalene , and its subsequent cyclization gives rise to cyclopentanoperhydrophenantherene skeleton containing steroidal compounds like cholesterols and other groups like triterpenoids .

Slide 25:

The acetate mevalonate pathway thus works through IPP and DMAPP via squalene to produce two different skeleton containing compounds, that is, steroids and triterpenoids . It also produces vast array of monoterpenoids , sesquiterpenoids , diterpenoids , carotenoids , polyprenols , and also the compounds like glycosides and alkaloids in association with other pathways.

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