Decoding Isoprenoid Biosynthesis: Mevalonate, MEP Pathways, and Terpenoid Classification

 Introduction to Terpenoids

Terpenoids, also referred to as isoprenoids, constitute a vast and diverse class of natural compounds found abundantly throughout the plant and microbial kingdoms. These compounds have captivated researchers for their remarkable structural diversity and wide-ranging biological activities. Derived from terpenes, terpenoids play pivotal roles in various ecological interactions, including plant defence mechanisms, communication between organisms, and as essential components of aromatic oils.

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Terpenes and Terpenoids: Understanding the Relationship

Terpenes and terpenoids are closely related compounds found abundantly in nature, particularly in plants, fungi, and some bacteria. While they share similarities in structure and biosynthesis, there are distinctions between the two that are important to understand.

Terpenes: Terpenes are a large and diverse class of organic compounds consisting of multiple isoprene units CH2​=C(CH3)CH=CH2, typically containing 10 to 30 carbon atoms. Isoprene, a five-carbon molecule, serves as the fundamental building block for terpenes. Terpenes are often volatile and contribute to the characteristic aromas and flavours of plants, fruits, and flowers. Examples of common terpenes include limonene, pinene, and myrcene, which are responsible for the distinct scents of citrus fruits, pine trees, and hops, respectively.

Terpenoids: Terpenoids, also known as isoprenoids, are derivatives of terpenes that have undergone chemical modifications, such as oxidation or rearrangement. These modifications often result in structural variations and increased complexity compared to their parent terpenes. Terpenoids exhibit a wide range of biological activities and are known for their pharmacological properties, including antimicrobial, antiviral, anti-inflammatory, and anticancer effects. Examples of terpenoids include menthol, taxol, and artemisinin, which are used in various medicinal applications.

Relationship between Terpenes and Terpenoids: Terpenoids are derived from terpenes through enzymatic or chemical transformations. These modifications can occur naturally within living organisms or through external processes such as extraction and chemical synthesis. While all terpenoids are derived from terpenes, not all terpenes are considered terpenoids. Terpenoids represent a subset of terpenes that have undergone specific chemical modifications, resulting in compounds with diverse structures and biological activities.

The discovery of terpenoids is a cumulative effort spanning centuries, involving various civilizations and scientific advancements. While no single individual is credited with their discovery, early civilizations, including the Egyptians, Greeks, and Romans, recognised the aromatic and medicinal properties of terpenoid-rich essential oils. In the 19th and 20th centuries, scientists like Otto Wallach and Leopold Ruzicka made significant contributions to understanding terpenoid structures and synthesising them. Wallach's work in structural elucidation and classification earned him the Nobel Prize in Chemistry in 1910, while Ruzicka's synthesis of terpenoids, including testosterone, led to his Nobel Prize in 1939. .

Essential Oil: Definition and Extraction

Essential oil refers to a concentrated hydrophobic liquid containing volatile aromatic compounds extracted from plants. These oils capture the plant's scent or "essence," and are renowned for their distinctive fragrances and therapeutic properties. Essential oils are used in various applications, including aromatherapy, perfumery, cosmetics, and alternative medicine.

Extraction Methods:

1. Steam Distillation:

2. Expression or cold pressing:

3. Solvent Extraction:

4. Carbon Dioxide (CO2) Extraction:

Classification of terpenoids:

1. Hemi-terpenoids (C5)
2. Mono-terpenoids (C10)
3. Sesquiterpenoids (C15)
4. Diterpenoids (C20)
5. Sesterterpenoids (C25)
6. Triterpenoids (C30)
7. Tetraterpenoids (C40)

1. Hemi-terpenoids (C5)

Hemi-terpenoids (C5) are a class of terpenoids that consist of five carbon atoms. They are characterised by their simple structure, which often includes a single isoprene unit. Due to their small size, hemi-terpenoids are less common compared to larger terpenoids, but they still possess biological activities and are found in various natural sources.

Examples of hemi-terpenoids include isoprene itself, as well as compounds like isovaleraldehyde and isopentanol. These molecules play roles in signalling, defence mechanisms, and biochemical pathways within organisms. Despite their simplicity, hemi-terpenoids contribute to the overall diversity and functionality of terpenoids in nature.

1. Mono-terpenoids (C10)

Mono-terpenoids (C10) are a class of terpenoids composed of ten carbon atoms. They are derived from two isoprene units and are characterized by their diverse structures and biological activities. Mono-terpenoids are commonly found in essential oils and resinous exudates of plants, where they contribute to the distinctive aromas and flavours of various botanical species.

Examples of mono-terpenoids include:

1. Limonene is a cyclic monoterpene commonly found in citrus fruits such as oranges, lemons, and limes. Limonene is used as a flavouring agent in food and beverages and as a fragrance in perfumery and household products. It also exhibits antioxidant and antimicrobial properties.

2. α-Pinene and β-Pinene: These are two isomeric forms of pinene, a bicyclic monoterpene found in the essential oils of many coniferous trees, including pine trees. α-pinene has a pine-like aroma, while β-pinene has a woody scent. Both compounds have demonstrated anti-inflammatory and bronchodilator effects.

3. Geraniol is a monocyclic monoterpene alcohol found in rose oil, citronella oil, and other floral essential oils. Geraniol is used in perfumery and flavouring due to its pleasant, rose-like scent. It also possesses insect repellent properties.

4. Sesquiterpenoids (C15)

   Sesquiterpenoids are a class of terpenoids composed of fifteen carbon atoms, derived from three isoprene units. They exhibit a diverse range of structures and biological activities, often found in essential oils and resinous exudates of plants.

   Examples of sesquiterpenoids include:

   1. Artemisinin is a sesquiterpene lactone derived from the plant Artemisia annua, commonly known as sweet wormwood. Artemisinin is used as a potent antimalarial drug due to its ability to kill malaria parasites.

   2. β-Caryophyllene is a bicyclic sesquiterpene found in many essential oils, including black pepper, cloves, and cannabis. It exhibits anti-inflammatory and analgesic properties and acts as a selective agonist of the cannabinoid receptor CB2.

   3. Farnesene is a linear sesquiterpene commonly found in the essential oils of fruits such as apples. It contributes to the characteristic aroma of apples and is also used as a flavouring agent.

   Diterpenoids (C20)

   Diterpenoids are terpenoids composed of twenty carbon atoms, derived from four isoprene units. They are structurally diverse and play various roles in plant defence, signalling, and secondary metabolism.

   Examples of diterpenoids include:

   1. Taxol (Paclitaxel): a complex diterpene alkaloid isolated from the Pacific yew tree (Taxus brevifolia). Taxol is a potent anticancer agent used in the treatment of ovarian, breast, and lung cancers.

   2. Gibberellins: a group of diterpenoid plant hormones that regulate growth and development processes such as seed germination, stem elongation, and flowering.

   3. Cafestol and Kahweol: Diterpene compounds found in coffee beans that contribute to the flavour and aroma of coffee. They also possess potential health benefits, including antioxidant and anticancer properties.

   Sesterterpenoids (C25)

   Sesterterpenoids are terpenoids composed of twenty-five carbon atoms, derived from five isoprene units. They are less common compared to other terpenoids but display significant structural diversity and biological activities.

   Examples of sesterterpenoids include:

   1. Sesterstatin is a sesterterpenoid compound isolated from the marine fungus Aspergillus terreus. Sesterstatin exhibits potent cytotoxic activity against cancer cells.

   2. Sarcodonin is a sesterterpenoid lactone found in the fungus Sarcodon species. It possesses antibacterial and antifungal properties and shows potential as a therapeutic agent against microbial infections.

   3. Briarellin is a sesterterpenoid compound isolated from marine organisms such as the coral Briareum species. Briarellins exhibit cytotoxic and antifungal activities.

   Triterpenoids (C30)

   Triterpenoids are terpenoids composed of thirty carbon atoms, derived from six isoprene units. They are abundant in nature and exhibit a wide range of biological activities, including anti-inflammatory, anti-cancer, and hepatoprotective effects.

   Examples of triterpenoids include:

   1. β-Sitosterol is a common triterpenoid found in plant oils, seeds, and nuts. β-Sitosterol exhibits cholesterol-lowering properties and is used in the treatment of benign prostatic hyperplasia and other medical conditions.

   2. Ginsenosides: are triterpene glycosides found in the roots of Panax ginseng and other Panax species. Ginsenosides have adaptogenic properties and are used in traditional medicine to enhance physical and mental performance.

   3. Ursolic acid is a pentacyclic triterpenoid found in various plant species, including apple peels, rosemary, and basil. Ursolic acid exhibits anti-inflammatory, antioxidant, and anticancer activities.

   Tetraterpenoids (C40)

   Tetraterpenoids are terpenoids composed of forty carbon atoms, derived from eight isoprene units. They are characterised by their extensive conjugated double bond systems and are primarily found in photosynthetic organisms, where they play essential roles in photosynthesis and photoprotection.

   Examples of tetraterpenoids include:

   1. Carotenoids are pigmented tetraterpenoid compounds found in fruits, vegetables, and algae. Carotenoids, such as β-carotene, lycopene, and lutein, serve as antioxidants and precursors of vitamin A.

   2. Phylloquinone (Vitamin K1): a tetraterpenoid compound found in green leafy vegetables. Phylloquinone is essential for blood clotting and bone metabolism.

   3. Phytoene is a colourless tetraterpenoid compound and precursor in the biosynthesis of carotenoids. Phytoene plays a crucial role in the regulation of photosynthesis and photoprotection in plants.

   Each class of terpenoids exhibits unique structural features and biological activities, contributing to their diverse roles in nature and potential applications in medicine, agriculture, and industry.

Polyterpenes           

Polyterpenes are long-chain polymers composed of repeating isoprene units. Unlike smaller terpenoids, which consist of a few isoprene units, polyterpenes can contain hundreds or even thousands of isoprene units linked together. These polymers can be linear or branched and often exhibit high molecular weights.

Polyterpenes are primarily found in natural rubber, which is produced by certain plants, such as Hevea brasiliensis (rubber tree), as a milky latex. The polymerization of isoprene units in the latex results in the formation of long polyisoprene chains, giving rubber its elastic properties. Natural rubber has numerous industrial applications, including in the production of tyres, seals, hoses, and adhesives.

Meroterpenes

Meroterpenes are hybrid compounds that contain both terpenoid and non-terpenoid structural elements. Unlike typical terpenoids, which are solely derived from isoprene units, meroterpenes incorporate additional functional groups or moieties into their structures through biosynthetic pathways.

Meroterpenes are found in various natural sources, including plants, fungi, and marine organisms, and exhibit diverse biological activities. These compounds often display unique pharmacological properties and have attracted attention in drug discovery and development.

Examples of meroterpenes include:

1. Artemisinin is a sesquiterpene lactone isolated from Artemisia annua (sweet wormwood). Artemisinin contains a peroxide bridge, which is not characteristic of typical terpenoids. It is used as an antimalarial drug.

2. Fungal meroterpenoids: These compounds are produced by fungi and contain both terpenoid and polyketide structural elements. Examples include fusarielins, which exhibit antifungal and cytotoxic activities.

3. Carotenoid-derived Meroterpenoids: These compounds are formed through the modification of carotenoids, which are tetraterpenoids. Meroterpenoids derived from carotenoids often contain additional functional groups, such as oxygen-containing moieties. Examples include retinoids, which are derivatives of β-carotene and have important roles in vision and cellular differentiation.

Biosynthesis of Isoprenoids: The Mevalonate and Methylerythritol Phosphate Pathways

a detailed overview of the biosynthesis of isoprenoids through both the mevalonate pathway and the methylerythritol phosphate (MEP) pathway, including the key enzymes involved and their locations within the cell:

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Mevalonate Pathway: in the Cytoplasm

1. Acetyl-CoA Formation:

   • Enzyme: Acetyl-CoA synthase
   • Location: Cytoplasm
   • Function: Catalyses the condensation of two molecules of acetyl-CoA to form acetoacetyl-CoA.

2. Formation of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA):

   • Enzyme: HMG-CoA synthase
   • Location: Cytoplasm
   • Function: Catalyses the condensation of acetoacetyl-CoA with a third molecule of acetyl-CoA to form HMG-CoA.

3. Reduction of HMG-CoA:

   • Enzyme: HMG-CoA reductase
   • Location: Endoplasmic reticulum (ER) membrane
   • Function: Catalyses the reduction of HMG-CoA to form mevalonate, using two molecules of NADPH as reducing equivalents.

4. Mevalonate Phosphorylation:

   • Enzyme: mevalonate kinase
   • Location: Cytoplasm
   • Function: Catalyses the phosphorylation of mevalonate to form mevalonate-5-phosphate, utilising ATP as a phosphate donor.

5. Formation of IPP and DMAPP:

   • Enzyme: Mevalonate diphosphate decarboxylase (MDD)

   • Location: Cytoplasm

   • Function: catalyses the decarboxylation of mevalonate-5-phosphate to form IPP (isopentenyl diphosphate).

   • Enzyme: Isopentenyl diphosphate isomerase (IDI)

   • Location: Cytoplasm

   • Function: Catalyses the isomerization of IPP to form DMAPP (Dimethylallyl diphosphate).

6. Formation of Longer Isoprenoid Chains:

   • IPP and DMAPP serve as the building blocks for the biosynthesis of longer isoprenoid chains, including geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP).

Methylerythritol Phosphate (MEP) Pathway:

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1. Formation of DOXP (1-deoxy-D-xylulose 5-phosphate):

   • Enzyme: DOXP synthase (DXS)
   • Location: Plastids
   • Function: Catalyzes the condensation of glyceraldehyde 3-phosphate (G3P) and pyruvate to form DOXP.

2. Formation of MEP (2-C-methyl-D-erythritol 4-phosphate):

   • Enzyme: DOXP reductoisomerase (DXR)
   • Location: Plastids
   • Function: Catalyzes the reduction and isomerization of DOXP to form MEP.

3. Formation of IPP and DMAPP:

   • Enzyme: MEP cytidyltransferase (IspD) and MEP synthase (IspE)

   • Location: Plastids

   • Function: Catalyzes the conversion of MEP to IPP and DMAPP.

   • Enzyme: HMBPP synthase (IspG) and HMBPP reductase (IspH)

   • Location: Plastids

   • Function: Catalyzes the conversion of HMBPP to IPP and DMAPP.

4. Formation of Longer Isoprenoid Chains:

   • IPP and DMAPP serve as the building blocks for the biosynthesis of longer isoprenoid chains, including geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP).

These pathways highlight the compartmentalization of isoprenoid biosynthesis, with distinct enzymatic reactions occurring in different cellular locations, such as the cytoplasm and plastids. This spatial organization facilitates the efficient synthesis and regulation of isoprenoid precursors and allows for the diverse array of isoprenoid compounds found in living organisms.

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