Biosynthesis of Lipids IV

Suaib Luqman

epgp books
  1. Objectives
  • v To understand the biosynthesis of isoprenoids and / or terpenoids
  • v How do mevanolate and non-mevanolate pathway operates
  1. Concept Map
  1. Description

 

Isoprenoids and/or Terpenoids Biosynthesis

 

 

Isoprenoids more often called as terpenoids are organic chemicals (hydrocarbons) of diverse class derived from 5C isoprene units (CH2=C (CH3) CH=CH2) amassed and customized in ad infinitum. They are mostly multicyclic structures that not only differ in their basic carbon skeletons but also in functional groups. These lipids contribute the biggest group of natural products (60%) and present in each and every class of living things.

Terpenoids isolated from the plants are being used comprehensively for their aromatic traits and play a significant role in traditional herbal remedies besides anti-neoplastic, anti-microbial and additional pharmaceutical utility. They contribute to the flavors of ginger, cloves and cinnamon, eucalyptus scent, red color of tomatoes and yellow color of sunflowers. Camphor, citral, menthol are some of the well-known terpenoids. Other includes curcuminoids (turmeric & mustard seed) salvinorin A (Salvia divinorum), cannabinoids (Cannabis spp.), bilobalide and ginkgolide (Ginkgo biloba). In animals, the sterols and steroids are biologically created from the precursors of the terpenoid. Occasionally, terpenoids enhances the attachment of proteins to the cell membrane by a process called isoprenylation. The presence of terpenoids can be identified by performing Salkowski test. Structurally they can be classified as under:

No. of Isoprene Units No. of Carbon Terpenoid Class Example
One Five Hemiterpenoids
Two Ten Monoterpenoids
Three Fifteen Sesquiterpenoids
Four Twenty Diterpenoids Ginkgolides
Five Twenty Five Sesterterpenoids
Six Thirty Triterpenoids Sterols
Eight Forty Tetraterpenoids Carotenoids

 

 

Polyterpenoid are the class contains a greater number of isoprene units and Meroterpenes are the compounds with a partial terpenoid structure. Following are the metabolic pathways reported for terpenoids biosynthesis and production.

 

Mevalonic Acid (MVA) Pathway

 

 

A lot of organisms assemble terpenoids through the MVA pathway also known as HMG-CoA reductase pathway or the Isoprenoid pathway that also make cholesterol. It is an indispensable metabolic pathway found in archaea, bacteria and eukaryotes. The alleyway produces two 5C building blocks called IPP and DMAPP that isoprenoids and more than 30,000 diverse class of biomolecules including vitamin K, steroids, heme, coenzyme Q10 and cholesterol. The MVA pathway was discovered in 1950s and the reactions occur in the cytosol of the cells. The pathway embarks with Acetyl CoA and ends with the formation of IPP and DMAPP. The first three steps of the MVA pathway are referred as upper MVA pathway (i.e. acetyl Co A to mevanolate) and rest of the steps of the pathway are called lower MVA pathway (i.e. mevanolate to IPP/DMAPP).

 

The MVA pathway of archaea, bacteria and eukaryotes begins in the similar way as the Acetyl CoA is the feed stock of the pathway. The steps of the upper MVA pathway are as under:

1.      Two Acetyl CoA molecules yield an Acetoacetyl CoA.

2.      Condensation of Acetoacetyl CoA to form 3-hydroxy-3-methyl-glutaryl-CoA (HMG CoA).

3.      Reduction of HMG CoA to form Mevalonate.

 

 

In lower MVA pathway, conversion of mevalonate to IPP and DMAPP has three reported variants.

 

  1. Mevalonate of eukaryotes is phosphorylated (5 OH position) twice followed by decarboxylation to yield IPP.
  2. Mevalonate of archaea (Haloferax volcanii) is phosphorylated (5 OH position) once followed by decarboxylation to yield IP and again phosphorylated to get IPP (Archaeal Mevalonate Pathway I).
  3. In Thermoplasma acidophilum, mevalonate is phosphorylated (3 OH followed by 5 OH position) to produce mevalonate 3, 5 bisphosphate and then decarboxylated to IP followed by formation of IPP (Archaeal Mevalonate Pathway II).

MVA Pathway Feedback and Regulation

 

 

A number of key enzymes can be activated in the course of DNA transcriptional regulation on the commencement of SREBP1 and SREBP2 (sterol regulatory element binding protein). Both the isoforms (SREBP1 and SREBP2), acting as an intracellular signals, perceive low cholesterol levels and kindle endogenous production by the HMG CoA reductase pathway through lipoprotein uptake increase and LDL receptor upregulation. The regulation of MVA pathway is also accomplished by scheming the translation rate of the mRNA, reductase degradation and phosphorylation.

 

A number of drugs including Statins (class of cholesterol lowering drug) targets the MVA pathway and Atorvastatin (Lipitor) inhibits HMG CoA reductase step. Bisphosphonates, another class of drugs targeting MVA pathway is used to take care of diverse bone degenerative diseases. The MVA kinase deficiency results in Hyper Immunoglobulinemia D Syndrome (HIDS) and Mevalonic Aciduria that affects MVA pathway.

 

Non-mevalonate or Alternative Pathway

 

In most of the bacteria, some protozoans (malaraia parasites) and plants, isoprenoids are produced by using an non-mevalonate or alternative pathway called the Methyl Erythritol Phosphate (MEP) pathway. The production of both the MVA and non-mevanolate (MEP) pathway are IPP and DMAPP, but the enzymatic reactions involved in the conversion of Acetyl CoA to IPP are utterly different. In higher plants, the MVA pathway maneuvers in the cytosol while the MEP pathway drives in plastids. Among bacteria, the MEP pathway operates in Escherichia coli and Mycobacterium tuberculosis.

 

The non-mevanolate pathway also known as the 2C methyl D erythritol 4 phosphate / 1 deoxy D xylulose 5 phosphate (MEP/DOXP) pathway or mevalonic acid-independent pathway occurs in many bacteria, apicomplexan of protozoans as well as in the plastids of plants. In 1980s, the pathway was discovered whose enzymatic steps are as under:

 

1.      DOXP synthase converts pyruvate and glyceraldehyde 3-phosphate to 1 deoxy D xylulose 5 phosphate.

2.      DOXP reductase forms 2C methyl D erythritol 4 phosphate (MEP).

  1. 2C methyl D erythritol 2, 4 cyclopyrophosphate (MEcPP) is produced due to the succeeding three reaction steps catalyzed by 4 diphosphocytidyl 2C methyl D erythritol synthase, 4 diphosphocytidyl 2C methyl D erythritol kinase and 2C methyl D erythritol 2, 4 cyclodiphosphate synthase.
  2. HMB-PP synthase converts MEcPP to (E) 4 hydroxy 3 methyl but 2 enyl pyrophosphate (HMB PP).
  3. HMB-PP reductase converts HMB-PP to IPP and DMAPP.

 

 

IPP and DMAPP are not only the end products of MVA and MEP pathways but also they serve as the precursors of isoprene units (5C), monoterpenoids (10C), diterpenoids (20C), carotenoids (40C), plastoquinone 9 and chlorophylls (45C). The synthesis of the entire higher terpenoids ensued by the configuration of GPP (geranyl pyrophosphate), FPP (farnesyl pyrophosphate) and GGPP (geranylgeranyl pyrophosphate). Even though, both MVA and MEP pathways are reciprocally elite in the majority of organisms, relations amid them have been testimonied in few species of bacteria and plants.

 

Pathway (s) Operated Organism
MVA Archaea, Fungi, Animals
MEP Green Algae, Protozoan
MVA or MEP Bacteria, Plants

 

 

The MVA or HMG CoA reductase pathway is a classical and an imperative metabolic pathway present in many bacteria and higher eukaryotes. It is vital for IPP and DMAPP production and dole out as the source for the biosynthesis of molecules employed in N-glycosylation and protein prenylation, maintenance of cell membrane, and protein anchoring. In contrast to the classical MVA pathway, most bacteria, some protozoans and plants fabricate their isoprenoids (terpenoids) using non-mevalonate (MEP) pathway.

 

 

DOXP reducto-isomerase, a key enzyme of non-mevalonate pathway, is specifically inhibited by Fosmidomycin and consequently signifies an attractive target for antimalarial drug or antibiotic. HMB PP, an intermediate of MEP/DOXP pathway, activates human Vγ9/Vδ2 T cells, a major γδ T cell population of peripheral blood.

 

  1. ummary

 

In this lecture we learnt about:

 

  • The Biosynthesis of Isoprenoids & Terpenoids
  • The MVA and the MEP/DOXP Pathway
you can view video on Biosynthesis of Lipids IV

 

Weblinks

 

 

Books

 

  1. Lehninger Principles of Biochemistry by David L. Nelson, ‎Albert L. Lehninger, ‎Michael M. Cox. 2008. https://books.google.co.in/books?isbn=071677108X
  2. Isoprenoid Synthesis in Plants and Microorganisms by Thomas J. Bach, ‎Michel Rohmer, 2012. https://books.google.co.in/books?isbn=1461440629
  3. Studies of plant terpenoid biosynthesis using 13C stable isotope labeling techniques by Andrea Ghirardo. 2011. https://books.google.co.in/books?isbn=3866446713
  4. The Organic Chemistry of Biological Pathways by John McMurry, ‎Tadhg P. Begley. 2005. Page 126 https://books.google.co.in/books?isbn=0974707716

 

Journals

 

  1. Buhaescu I, Izzedine H (2007) Mevalonate pathway: areview of clinical and therapeutical implications. ClinBiochem 40:575–584.
  2. Holstein, S. A., and Hohl, R. J. (2004) Isoprenoids: Remarkable Diversity of Form and Function. Lipids 39,‎293−309.
  1. Goldstein,‎J.‎L.,‎and‎Brown,‎S.‎B.‎(1990)‎Regulation‎of‎the‎mevalonate‎pathway.‎Nature‎343,‎425−430.