= HMG-CoA = == 3-hydroxy-3-methylglutaryl-coenzyme A - pathways == Adapted from figures on page 402 and 405 of Biochemistry of Lipids, Lipoproteins, and Membranes 5th Edition 2008 eds: Vance and Vance This is the molecular synthesis cascade interrupted by statins, HMG-CoA Reductase inhibitors, which attach to HMG-CoA Reductase and block further synthesis in order to reduce serum cholesterol and reduce atherosclerotic plaque and vascular disease. This stems from observations that red rice yeast reduced cholesterol, and that oxysterol deposits may correlate with plaque deposits, inflammation, and infarction (in overfed westerners). But correlation is not causation. The oxysterol association is indirect, observed ''in vitro'' but the ''in vivo'' studies are short term and contradictory. The inflammation may be due to stress and too many calories. The plaque may be the body's way of patching over the inflammation. Too many tire patches will render a tire stiff (hypertension), and too many inside patches will plug the pipe they are patching from the inside. But then, reasoning by analogy isn't really reasoning either, is it? Some claim that statins act as a poor analog for vitamin D (synthesized from cholesterol sulfate and sunshine) which is quite deficient in northern-latitude sunlight-poor indoor dwellers. Others claim that statins cause muscles to produce lactate which fuels the heart better than glucose. Lots of claims out there. '''In any case''', if what we are attempting to do is limit serum cholesterol, we should be blocking the synthesis of '''squalene''', not mevalonate. If what we are ''actually'' trying to do is lower LDL and VLDL cholesterol particles (which are cholesterol '''containers''', not merely cholesterol), we should inhibit the formation of those large low density containers, while protecting cholesterol in HDL containers. Stopping mevalonate synthesis at the beginning of this tree of molecular synthesis is like reducing traffic accidents by bombing steel mills; without cars there are fewer traffic accidents, without steel there are fewer cars, but there are more direct causes of those accidents than either cars or steel. We know a hell of a lot more about molecular biology than we did in 1971, when Akira Endo began studying Penicillium citrinum and the mevastatin it produced. This statin is a poison used by fungi to defend themselves from other organisms by damagining synthesis of cell walls and cytoskeletons. Damaged cell walls and cytoskeletons are bad for children and other living things. || molecule || made by || from molecule || ||<-3> || || Acetyl-CoA || Acetoacetyl-CoA Thiolase || Acetoacetyl-CoA || || HMG-CoA || HMG-CoA Synthase || Acetyl-CoA || || Mevalonate || HMG-CoA Reductase || HMG-CoA || [[http://en.wikipedia.org/wiki/Statin|statins]] block this step || || Mevalonate-5-P || Mevalonate Kinase || Mevalonate || || Mevalonate-5-PP || Phosphomeavalonate Kinase || Mevalonate-5-P || || '''Isopentenyl-PP''' || Mevalonate-5-PP Decarboxylase || Mevalonate-5-PP || makes Isopentyl adenosome tRNAs || || Dimethylallyl-PP || Isopentenyl-PP Isomerase || '''Isopentenyl-PP''' || || '''Geranyl-PP''' || Farnesyl Diphosphate Synthase || Dimethylallyl-PP || makes Prenylated proteins, Heme A, Dolichol || || '''Farnesyl-PP''' || Farnesyl Diphosphate Synthase || '''Geranyl-PP''' || makes Ubiquinone/CoQ,,10,, || || Squalene || Squalene Synthase || '''Farnesyl-PP''' || '''why not block this step instead???''' || || Squalene epoxide || Squalene Epoxidase || Squalene || '''or block this step?''' || || Lanosterol || Oxidosqualene Cyclase || Squalene epoxide || '''or block this step?''' || || Zymosterol || || Lanosterol || '''or block this step?''' || ||<-3:>''postulated alternative pathway 1'' || || Cholest-8(9)-en-3β-ol || Δ24-reductase || Zymosterol || || Lathosterol || Δ8Δ7-isomerase || Cholest-8(9)-en-3β-ol || || 7-Dehydrocholesterol || Lanosterol Oxidase || Lathosterol || || '''Cholesterol''' || Δ7-DHC Reductase || 7-Dehydrocholesterol || ||<-3:>''postulated alternative pathway 2'' || || Cholesta-7,24-dien-3β-ol || Δ8Δ7-isomerase || Zymosterol || || 7-Dehydrodesmosterol || Δ5-desaturase || Cholesta-7,24-dien-3β-ol || || Desmosterol || Δ7-reductase || 7-Dehydrodesmosterol || || '''Cholesterol''' || Desmosterol Δ24-reductase || Desmosterol || ||<-3:><
>'''Also made from Mevalonate, suppressed by statins''' || ||'''[[http://en.wikipedia.org/wiki/Isopentenyl_pyrophosphate|Isopentenyl-PP]]'''||{{http://upload.wikimedia.org/wikipedia/commons/thumb/8/8a/Isopentenyl_pyrophosphate.svg/200px-Isopentenyl_pyrophosphate.svg.png | | width=200}}|| || ||Isopentenyl ? || || || ||adenosine ? || || || ||tRNAs ? || || || || || || || ||<-3> || ||'''[[http://en.wikipedia.org/wiki/Geranyl_pyrophosphate|Geranyl-PP]]'''||{{http://upload.wikimedia.org/wikipedia/commons/thumb/f/f0/Geranyl_pyrophosphate.png/320px-Geranyl_pyrophosphate.png | | width=200}}|| || ||[[http://en.wikipedia.org/wiki/Prenylation|Prenylated proteins]]|| || || ||[[http://en.wikipedia.org/wiki/Heme_A|Heme A]] || || || || || || || ||<-3> || ||'''[[http://en.wikipedia.org/wiki/Farnesyl_pyrophosphate|Farnesyl-PP]]'''||{{http://upload.wikimedia.org/wikipedia/commons/thumb/5/53/Farnesyl_pyrophosphate.png/320px-Farnesyl_pyrophosphate.png | | width=200}}|| || ||[[http://en.wikipedia.org/wiki/Ubiquinone|Coenzyme Q,,10,,]]|| || || ||[[http://en.wikipedia.org/wiki/Dolichol|Dolichol]] || || || || || || || ------ == Random quotes from "Biochemistry of Lipids ..." == ---- === Chapter 21 Lipids and atherosclerosis, Ira Tabas, Columbia === P590 section 3.3: The proposed roles of oxysterols in theirosclerosis are based primarily on the results of cell-culture experiments. There are a number of in vivo studies in which investigators have exposed animals to oxysterols through diet or injection, but the overall results are not conclusive. ... [18] of 13 oxysterol dietary studies, 6 showed an increase in atherosclerosis, but 4 demonstrated a decrease in lesion size and 3 showed no effect. ... P591 ... the concentrations of oxysterols used in most macrophage cell-culture studies far exceeds those found in macrophage foam cells in vivo. [19] .[18] Llodra ... 2004. Emigration of monocyte-derived cells from atherosclerotic ... J. Clin. Invest. 58: 200-211 .[19] Brown and Jessup, 1999. Oxysterols and atherosclerosis. Atherosclerosis 142: 1-28