04.03 - Cooper - Cholesterol Biosynthesis and Regulation

04.03 - Cooper - Cholesterol Biosynthesis and Regulation -...

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Cholesterol Biosynthesis and Regulation •Dr. Arthur J. L. Cooper •Room A17 •x3330 1 Historical Background Structure determined in the 1930s. In the late 1930s, Rudolf Schoenheimer , David Rittenberg and colleagues at Columbia University determined that acetate is a precursor of sterols by using acetate labeled with 2 H (deuterium). 1942 – posthumous publication of Schoenheimer’s book “ Dynamic State of Body Constituents ”. ~1950 Konrad Bloch (Columbia, Chicago then Harvard) and colleagues showed by using [ 14 C]acetate that all the C atoms of ergosterol are derived from acetate. In 1964 Konrad Bloch and Feordor Lynen (Munich) were awarded the Nobel prize for their studies on the overall biosynthetic pathway for cholesterol and steroid hormones. 2 Cholesterol Synthesis – Basic Modules Michael King - Indiana School of Medicine - www.med.unibs.it/~marchesi/cholest.html 3
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Module 1 – Mevalonate Synthesis synthase Isolated from red yeast rice Traditional Chinese medicine Notes : HMG-CoA for ketone body formation occurs in the mitochondria. HMG-CoA for cholesterol biosynthesis occurs in the cytosol – Two distinct isozymes of HMG-CoA synthase the mitochondrial isozyme is controlled by succinylation. Most of the remaining cholesterol synthesizing enzymes are in the ER. Thiolase and HMG-CoA reductase catalyze Claisen condensations 4 Some EFects of Statins at the Cellular Level 5 Defect in mevalonate kinase causes a rare recessive inborn error of metabolism – mevalonate aciduria ±arnesyl pyrophosphate (C15) can be used to generate geranylgeranyl pyrophosphate (C20) by condensation with isopentenyl pyrophosphate. Both farnesyl pyrophosphate and geranylgeranyl pyrophosphate can be used in the isoprenylation of terminal cysteine residues in some proteins e.g. Rho and Ras . 5C 5C 10C 15C 6C Module 2 – ±arnesylpyrophosphate Synthesis 6
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Nomenclature of 5-C units CH 3 C(=CH 2 )CH 2 CH 2 - is an isopentenyl unit CH 3 C(=CH 2 )CH=CH 2 is an isoprene molecule The empirical formula (C 5 H 8 ) n was Frst deduced by ±araday in 1829 for the natural isoprene polymer rubber! 5-C, 10-C, 15-C and 30-C intermediates in cholesterol synthesis may be regarded as either derived from isopentyl units or formally regarded as polymers of isoprene molecules. Any compound derived from isoprene units is known as a terpenoid – 55,000 have been described thus far and hundreds are characterized each year! Note
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04.03 - Cooper - Cholesterol Biosynthesis and Regulation -...

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