Biosynthesis of Lipids III

Suaib Luqman

epgp books
  1. Objectives

 

  • v To understand the biosynthesis of steroids
  • v How do cholesterol, cortisol and testosterone synthesize

 

  1. Concept Map

3. Description

 

Biosynthesis of Steroid

 

 

It is an anabolic metabolic alleyway which utilizes simple precursors to make steroids. In animals and several other living organisms, this conduit is being carried out in discrete ways making it a frequent target for anti-infective agents and other antibiotics. Furthermore, in humans, statins, the cholesterol lowering drugs targets steroid metabolism. It starts with the Acetyl CoA in the MVA pathway as building blocks that configure IPP and DMAPP followed by the formation of lanosterol, the first steroid. Additional modifications give rise to the ensuing steroidogenesis.

 

Steroidogenesis is the natural course of action by which steroids are enkindled from cholesterol and gets altered into several other steroids. The biosynthetic pathways of steroidogenesis vary amid distinct species, but in humans, the products of the biosynthetic pathways of steroidogenesis include: aldosterone, androgens, corticoids, cortisol, estrogens, progesterone and testosterone.

 

Biosynthesis of Cholesterol

 

 

Cholesterol is predominantly vital molecule of class sterols with a hydroxyl group and four fused rings. Being an important constituent of lipid membranes, cholesterol also act as a predecessor to numerous steroid hormones comprising cortisol, estrogen and testosterone. In animals, cholesterol produced with a relative speed anecdotal to the type of cell and function of the organ. In liver, a propos of 20-25% cholesterol production occurs daily. Adrenal glands, Intestines and Reproductive organs are the other sites of higher synthesis. It is synthesized from Acetyl CoA in numerous conversions as shown below.

 

 

·  One molecule each of Acetyl CoA and Aceto-acetyl CoA dehydrated to delineate 3-hydroxy-3-methylglutaryl CoA (HMG CoA). The reaction was catalyzed by Thiolase and HMG CoA synthase.

 

·    HMG CoA is reduced to mevalonate (MVA) by HMG CoA reductase enzyme. This is a rate limiting and regulatory step irreversible in cholesterol biosynthesis. Statin (competitive inhibitor of HMG CoA reductase) drugs targets this step for their action.

· MVA is further converted to mevalonate-5-phosphate and mevalonate-5-pyrophosphate with the aid of enzyme Mevalonate kinase and Phosphomevalonate kinase respectively.

 

·Mevalonate-5-pyrophosphate decarboxylase converts mevalonate-5-pyrophosphate to isopentenyl pyrophosphate (IPP) in a reaction that requires ATP. IPP is a crucial metabolite for diverse biological reactions.

 

·  IPP (3 molecules) condense to structure geranyl pyrophosphate (GPP) and farnesyl pyrophosphate (FPP) by the accomplishment of Geranyl transferase and Farnesyl pyrophosphate synthase respectively. Isopentenyl pyrophosphate isomerase converts IPP to Dimethyl allyl pyrophosphate (DMAPP) which further forms GPP and FPP. Bisphosphonates inhibits the steps of GPP and FPP conversions.

 

·         FPP (2 molecules) subsequently deliquesce to create squalene through the deed of squalene synthase in the endoplasmic reticulum. Also FPP forms Geranylgeranyl pyrophosphate by the action of enzyme Geranylgeranyl pyrophosphate synthase which give rise to prenylated proteins.

·         Squalene monooxygenase coverts squalene to 2,3-oxidosqualene and Squalene epoxidase or Oxidosqualene cyclase further cyclizes squalene to structure lanosterol.

·         Ultimately, lanosterol is subsequently transformed to cholesterol.

 

 

In 1964, Konrad Bloch & Feodor Lynen shared the Nobel Prize in Physiology & Medicine for their discoveries pertaining to the regulation of fatty acid metabolism and cholesterol mechanism. In general, the cholesterol biosynthesis crop up in three stages: (1) Occurs in the cytoplasm (2) & (3) in endoplasmic reticulum. The stages are as under:

  1. Biosynthesis of IPP, the ‘building block’ of cholesterol.
  2. Genesis of squalene through the abridgment of IPP.

Translation of squalene into cholesterol by a number of enzymatic reactions

 

Regulation of Cholesterol Biosynthesis

 

 

It is unswervingly regulated by the level and concentration of cholesterol present, albeit the mechanism of homeostasis involved are merely understood. A high intake of cholesterol rich food leads to a decline in endogenous production, whereas lower intake has the oppugning outcome. Sterol regulatory element binding protein 1 & 2 (SREBP) is the main regulatory protein that sense the intracellular cholesterol level in the endoplasmic reticulum. In the charisma of cholesterol, two other proteins namely SREBP cleavage activating protein (SCAP) and Insig1 were found bound to SREBP. When the level and concentration of cholesterol goes down, Insig 1 separate from the SREBP-SCAP complex, allowing it to drift towards Golgi complex, where Site 1 (S1P) and Site 2 (S2P) proteases cleaved SREBP. The S1P and S2P get activated by SCAP when the concentration and level of cholesterol becomes low. The smited SREBP further transfers to the nucleus and work as a transcription factor to truss with sterol regulatory element (SRE) which kindle the transcription of numerous genes (e.g. HMG CoA reductase and low density lipoprotein receptor). HMG-CoA reductase leads to an enhancement of endogenous cholesterol production whereas LDL receptor scavenges flowing LDL from the bloodstream. In 1970s, Dr. Michael S. Brown & Dr. Joseph L. Goldstein clarified this conundrum and they received the Nobel Prize in Physiology & Medicine for their effort in 1985. Subsequently, they showed the expression and regulation of numerous genes by the SREBP pathway that manages lipid formation and metabolism and its allocation in body fuel. High level and concentration of cholesterol shuts off the biosynthesis. The enzyme HMG CoA reductase includes a membrane and a cytosolic domain (liable for its catalytic activity). The membrane domain functions to sense signals for its degradation. Increase in the level and concentration of cholesterol or other sterols effectuate a change in the oligomerization state of the domain that makes it further susceptible to proteasome annihilation. The enzyme’s activity can also be diminished by AMP activated protein kinase phosphorylation. When ATP hydrolyzed, AMP is formed which activate kinase functions and cholesterol biosynthesis remains halted as long as ATP level becomes low.

 

Cortisol Biosynthesis

 

 

In humans, cortisol, a glucocorticoid class of steroid hormone, is produced by the zona fasciculata of the cortex region of adrenal gland. It is also biosynthesized from cholesterol. The cortical region of adrenal gland especially zona glomerulosa produces aldosterone, zona reticularis produces sex hormones while medullary region of the adrenal gland lies beneath the cortex, primarily secretes the catecholamines namely: epinephrine (adrenaline) and norepinephrine (noradrenaline) under considerate stimulus. The cortisol biosynthesis is invigorated by adrenocorticotropic hormone (ACTH) secreted by the anterior lobe of the pituitary gland. The production of ACTH is vitalized by corticotrophin releasing hormone (CRH) discharge by the hypothalamus. Increase in ACTH concentration, increases the cholesterol level in the inner mitochondrial membrane through the regulation of the steroidogenic acute regulatory (STAR) protein thereby stimulating the major rate limiting step (cholesterol conversion to pregnenolone) in cortisol biosynthesis catalyzed by Cytochrome P450 side chain cleavage enzyme (CYP450 SCC).

 

As far as metabolism of cortisol is concerned, it gets metabolized via 11-β hydroxysteroid dehydrogenase system (11-β HSD) possessing two isoform of the enzymes: 11-β HSD1 and 11-β HSD2.

 

·   The former 11-β HSD1 make use of NADPH and metamorphose it to biologically inert cortisone followed by final transformation to active cortisol.

·   11-β HSD2 exploit NAD+ to change cortisol to cortisone.

 

By and large, 11-β HSD1 dole out to augment the limited concentrations of cortisol and 11-β HSD2 decreases the restricted concentrations of cortisol.

 

Furthermore, cortisol is also metabolized to 5α tetrahydrocortisol (5α THF) and 5β tetrahydrocortisol (5β THF) via catalytic activity of 5α reductase and 5β reductase, the enzymes adjudged as the rate-limiting factors. 5β reductase is also acts as the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone. It has also been suggested that modification of 11-β HSD1 play an important role in the pathogenesis of hypertension, insulin resistance and obesity, while 11-β HSD2 alteration has been implicated in essential hypertension and is acknowledged to escort to the syndrome of apparent mineralocorticoid excess (SAME).

 

Testosterone Biosynthesis

 

 

Similar to that of other steroidal hormones, testosterone is also gleaned from cholesterol. The step by step biosynthesis is described as under:

 

1.  It engross the oxidative cleavage of cholesterol side chain by CYP11A (mitochondrial cytochrome P450 oxidase) with the trouncing of 6C units to bestow pregnenolone.

 

2. In ER, 2C atoms get obliterated by CYP17A enzyme to yield an assortment of C19 steroids. In toting up, the 3-hydroxyl group is oxidized by 3β HSD to generate androstenedione.

3.The final step is the rate limiting step where 17β hydroxysteroid dehydrogenase reduces androstenedione (C17 keto group) to yield testosterone.

In men, the testis (leydig cells) produces high amount (>95%) of testosterone while in women it is also synthesized in extremely lesser quantity by by placenta, ovarian thecal cells as well as by the cortical region

 

 

(zona reticularis) of adrenal gland in both sexes. Sertoli cells which are a part of the male generative glands also require testosterone for spermatogenesis. Similar to that of other hormones, in blood testosterone is afforded to target tissues where a large amount of it is elated to sex hormone binding globulin (SHBG, a specific plasma protein).

 

Steroids and its exploitation

 

 

In 1930s, anabolic steroids were first isolated, identified and synthesized and are nowadays used in medicine for therapeutic purpose to kindle appetite, bone growth, male puberty and to take care of chronic wasting conditions like AIDS and cancer. Anabolic steroids also increases mass of the muscle and augment physical strength therby promoting its usage in bodybuilding and sports to boost physique and/or strength. Besides advantages, anabolic steroids have some known side effects such as acne formation, high blood pressure, increase LDL, decrease HDL, liver damage etc which can be alleviated by captivating supplemental drugs.

In 1954, the use of anabolic steroid begins in sports. John Ziegler (doctor of American athletes) met a Russian physicist in Vienna who was giving testosterone in drinks to the weight lifters for enhancing the performance. On return, Ziegler tried testosterone (weak dose) on himself, Bob Hoffman (trainer), Jim Park and Yaz Kuzahara (two lifters). Besides the weight gain and strength enhmancement there were side effects of the testetosterone noticed. In 1958, Ziegler hit on methandrostenolone (Dianabol) prepared in the United States by Ciba. Thereafter, with impressive results, anabolic steroids spread to other sports including American football, shot put, steeplechase, discus throw etc.

 

 

In 1972 Olympics, the range of steroid use was from 10-100 mg per day. In 1988, Ben Johnson Olympic victory in the 100 m race becomes a popular story as he failed the drug test. Stanozolol was found in his urine and he confessed that he has used Cypionate, Dianabol, Furazabol, Human growth hormone and Testosterone for performance enhancement. Johnson was consequently stripped of his gold medal and Carl Lewis was subsequently promoted to receive the Olympic gold medal and title.

 

 

 

  1. Summary

 

In this lecture we learnt about:

 

  • The Biosynthesis of Lipids II
  • Biosynthesis of cholesterol
  • Biosynthesis of Cortisol
  • Biosynthesis of Testosterone
  • Steroids and its exploitation
you can view video on Biosynthesis of Lipids III

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. Regulation of Steroid Metabolism and the Hepatic …by Carla de Azevedo Piccinato. 2008. https://books.google.co.in/books?isbn=1109046324
  3. Cholesterol Metabolism, LDL, and the LDL Receptor by N Myant. 2012. Page 27 https://books.google.co.in/books?isbn=0323148875
  4. Cellular Lipid Metabolism by Christian Ehnholm. 2009. https://books.google.co.in/books?isbn=3642003001
  5. Testosterone: Action, Deficiency, Substitution by Eberhard Nieschlag, Hermann‎ M. Behre, Susan‎ Nieschlag. 2012. Page 23 https://books.google.co.in/books?isbn=1107012902
  6. Principles and Practice of Endocrinology and Metabolism by Kenneth L. Becker. 2001 https://books.google.co.in/books?isbn=0781717507