OIA2007 MEVALONIC ACID PATHWAY

MVA Pathway

A biosynthetic pathway leading to the formation of isoprenoids (terpenoids, cholesterol, steroids).

Where does MVA Pathway occur?

Cytosol of eukaryotic cells, plants, fungi, and some bacteria.

Primary Function (MVA Pathway)

Produces isoprene units (IPP & DMAPP) → precursors to terpenes, steroids, and cholesterol.

Precursor Molecules

Acetyl-CoA from glycolysis and pyruvate metabolism.

Step 1: Acetyl-CoA → Acetoacetyl-CoA

Enzyme: Acetyl-CoA acetyltransferase.

Step 2: Acetoacetyl-CoA → HMG-CoA

Enzyme: HMG-CoA synthase.

Step 3: HMG-CoA → Mevalonic Acid (MVA)

Enzyme: HMG-CoA reductase

Rate-limiting step, target of statins (e.g., simvastatin).

Step 4: Mevalonic Acid (MVA) → Mevalonate-5-Phosphate

Mevalonate-5-Phosphate → Mevalonate-5-Pyrophosphate (PP)

Step 5: Mevalonate-5-PP → Isopentenyl Pyrophosphate (IPP)

Via decarboxylation + ATP.

Step 6: IPP ⇌ Dimethylallyl Pyrophosphate (DMAPP)

Enzyme: IPP isomerase.

Isoprene Unit

Basic C5 unit (2-methyl-1,3-butadiene).

C5: Hemiterpenes

Smallest terpenes (e.g., isoprene as photosynthesis byproducts & prenol as flavouring).

C10: Monoterpenes

2 isoprene units (e.g., menthol in peppermint, citral in lemongrass, camphor in camphor wood).

C15: Sesquiterpenes

3 isoprene units (e.g., α-selinene in celery & β-Caryophyllene in clove oil).

C20: Diterpenes

4 isoprene units (e.g., Vitamin A in carrot & Gibberillins in plant hormones).

C25: Sesterterpenes

5 isoprene units (rare; found in marine sponges & mollusks).

C30: Triterpenes

6 isoprene units (e.g., squalene, steroids).

C40: Tetraterpenes

8 isoprene units (e.g., β-carotene in carrots, lycopene in tomatoes).

IPP (C5) + DMAPP (C5) → GPP (C10)

By Geranyl pyrophosphate synthase.

GPP (C10) + IPP (C5) → FPP (C15)

By Farnesyl pyrophosphate synthase.

FPP (C15) + FPP (C15) → Squalene (C30)

By Squalene synthase.

Squalene → Lanosterol → Cholesterol

Via cyclization, demethylation, isomerization.

Menthol

Monoterpene from peppermint (cooling agent).

Citral

Monoterpene aldehyde from lemongrass (lemon scent).

α-Phellandrene

Monoterpene from eucalyptus.

α-Selinene

Sesquiterpene in celery oil.

Vitamin A (Retinol)

Diterpene → essential for vision and immunity.

β-Carotene

Tetraterpene precursor to Vitamin A.

Cholesterol

Synthesized from squalene via MVA pathway.

Steroid Hormones

Include progesterone, estradiol, testosterone.

Corticosteroids

From cholesterol: cortisone, cortisol.

Bile Acids

e.g., Deoxycholic acid, aid in fat digestion.

Statins Mechanism

Inhibit HMG-CoA reductase → ↓ cholesterol synthesis.

Examples of Statins

Simvastatin, Atorvastatin.

Herbal Sources of Terpenoids

Ginger (rhizome), cinnamon (bark), rose (petals).

MVA vs Shikimic Acid (Products

MVA: Terpenoids, steroids, carotenoids.

Shikimic: Phenylpropanoids, flavonoids, alkaloids.

MVA vs Shikimic (Metabolic Integration)

MVA links with glycolysis (via acetyl-CoA); Shikimate links with pentose phosphate pathway.

Metabolic Engineering

Plants/microbes modified to overproduce terpenoids or cholesterol precursors.

Drug Precursors

MVA pathway yields important intermediates for antiviral, anticancer, and anti-inflammatory agents.