Konrad Bloch (1972) - Control Aspects of Lipid Biosynthesis

Konrad Bloch (1972)

Control Aspects of Lipid Biosynthesis

Konrad Bloch (1972)

Control Aspects of Lipid Biosynthesis

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The world’s best-selling class of drugs, the statins, have been developed based on knowledge independently gained by Konrad Bloch and Feodor Lynen who shared the Nobel Prize in Physiology or Medicine in 1964 for their elucidation of the biosynthesis of cholesterol – an intracellular marathon involving more than 30 steps. While the launch of the first drug of this class, atorvastatin, lay still 32 years ahead when Bloch held his Nobel lecture, and the medical rationale for the application of statins still had to be established[1], he rightly anticipated their molecular target: „If the principle of negative feedback operates in sterol biosynthesis as it does in so many pathways, then the first specific step of the sequence should be rate limiting and it should be sensitive to cholesterol, the end product of the biosynthetic sequence. With these considerations in mind, attention has been focused on the reduction of hydroxymethylglutaryl-CoA to mevalonic acid as a likely control site.“[2] In the early 1970s, the Japanese biochemist Akira Endo succeeded in extracting the prototype of HMG-CoA inhibitors[3], which became known as statins. While these drugs globally have generated cumulative sales of between one third and half a trillion dollars as of today, Endo did not receive any royalty for his groundbreaking work.

Bloch is well aware of current applied research activities to control the biosynthesis of cholesterol when he lectures in Lindau in 1972, yet his basic research interest now primarily aims at understanding the function of cellular membranes, including the role cholesterol plays in their composition. „It has been recognized that we cannot understand or describe cellular activities without an intimate knowledge of the structure and function of cell envelopes or the membranes, which surround the cell content, and since lipids along with proteins are essential membrane components, lipids have attracted wide attention“ he says and explains to his audience the Fluid-Mosaic-Model of the cell membrane, which Singer and Nicholson had proposed just four months before[4]: Proteins are embedded in a fluid bilayer, partly integrated, partly peripherally attached, with sugar moieties anchored on many proteins of the outer surface, and in this fluid mosaic, both lipids and proteins diffuse laterally in the plane of the membrane.

Drawing on this brand-new model, Bloch briefly recalls why lipids are uniquely suited to provide the fluid medium of membranes: „The amphiphilic character appears to be the secret of the lipid molecule.“ He then discusses environmental temperature and the length of the hydrocarbon chain as major determinants of the phospholipid structure and hence the fluidity of the membrane and goes on to describe the fatty acid synthesis with its sequential action of a set of seven enzymes, a chain lengthening process with „some very intriguing features“, which „surprisingly comes to a rather abrupt halt at a length of 16 or 18 acids“. To explain and illustrate the complex mechanism of lipid biosynthesis, Bloch subsequently devotes most of the time of his talk to discuss his current research on the properties of the fatty acid synthetase from mycobacterium phlei, the results of which he would submit for publication a few weeks later[5]. Notwithstanding the substantial increase of our knowledge about the function of membranes and the physiological role of lipids since the 1970s, Bloch’s state-of-the-art-introduction about his research on a highly organized multi-enzyme complex allows a fascinating insight into the workshop of an eminent scientist.

Joachim Pietzsch

[1] The discovery of the LDL-receptor by Brown and Goldstein in 1973, for which they shared the Nobel Prize in Physiology or Medicine in 1985, was a milestone on this way.

[2] Konrad Bloch: The biological synthesis of cholesterol, p.97 http://www.nobelprize.org/nobel_prizes/medicine/laureates/1964/bloch-lecture.html

[3] Endo A, Kuroda M, Tsujita Y (December 1976). "ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium". Journal of Antibiotics (Tokyo) 29 (12): 1346–8.

[4] Singer SJ and Nicolson GL (Feb. 18, 1972). The Fluid Mosaic Model of the structure of cell membranes. Science 175: 720-731.

[5] Vance DE, Mitshuhashi O and Bloch K. Purification and properties of the fatty acid synthetase from Mycobacterium phlei. J. Biol. Chem. 1973, 248:2303-2309.

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