Bloch pathway

Animals accumulate cholesterol from then diet but are also able to biosynthesize It from acetate The pioneering work that identified the key intermediates m the com plicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich) corecipients of the 1964 Nobel Prize for physiology or... 

Rittenberg and Bloch showed in the late 1940s that acetate units are the building blocks of fatty acids. Their work, together with the discovery by Salih Wakil that bicarbonate is required for fatty acid biosynthesis, eventually made clear that this pathway involves synthesis of malonyl-CoA. The carboxylation of acetyl-CoA to form malonyl-CoA is essentially irreversible and is the committed step in the synthesis of fatty acids (Figure 25.2). The reaction is catalyzed by acetyl-CoA carboxylase, which contains a biotin prosthetic group. This carboxylase is the only enzyme of fatty acid synthesis in animals that is not part of the multienzyme complex called fatty acid synthase. 

Analysis of the details of the pathway was helped by the discovery by Nancy Bucher (1953) that cholesterol synthesis took place in cell-free post-mitochondrial supernatants. ATP, Mg2+ and NAD+ were required. Tchen and Bloch extended these findings to show that squalene could be formed anaerobically but the conversion of squalene to cholesterol was oxygen dependent, the oxygen of the intermediate lanosterol being derived from 8C>2 not H2180. It therefore became possible to focus either on the conversion of acetate to squalene or on the latter s cyclization to the sterol. 

Konrod E. Bloch and Feodor Lynen Physiology/Medicine Pathways of cholesterol biosynthesis... 

Work on the biosynthesis of cholesterol began in earnest after Rudolf Schoenheimer and David Rittenberg, at Columbia University, developed isotopic tracer techniques for the analysis of biochemical pathways. In 1941, Rittenberg and Konrad Bloch were able to show that deuterium-labeled acetate (C2H, COO ) was a precursor of cholesterol in rats and mice. In 1949, James Bonner and Barbarin Arreguin postulated that three acetates could combine to form a single five-carbon unit called isoprene. 

Steroids arc lieavily modifted triterpeues that are btoeyntheaized in orjEftnisms from the acyclic hydrocarbon aqualeiio (SSection 27.6). The-e ci pathway by which thia remarkable transformation is accomplished lengthy and complex, but the key steps have now been worked out, with notable contributions made by Konrad Bloch and John Cornforth, who received hJohcl Prizes for their eiforts. 

The protein kinase C (PKC) signaling pathway has been associated with modulation of A-methyl-D-aspartate (NMDA) receptor activity, motor behavior, learning, and memory, all of which are severely impaired in intoxication with sarin and similar OPs. There was a reduction in the immunoreactivity levels of betall-PKC and Zeta-PKC in the frontal cortex (up to 24 h), and in the striatum (up to 5 days) post-sarin exposure, in contrast to the increase in the immunoreactivity of both enzymes in the hippocampus or thalamus, following a IxLDso exposure to sarin. These observations suggest a role for both conventional and atypical PKC isozymes in OP-induced neuropathy in the rat and further support their role in cell death (Bloch-Shilderman et al., 2005). 

Pig, 4. An RF pulse initially rotates the magnetization away from the z-axis (i.e. thermal equilibrium) by, in this example, an angle of about 170°. In the absence of radiation damping effects the magnetization follows the normal relaxation pathway (—) back to the thermal equilibrium. However, in the presence of radiation damping, the magnetization retains its coherence and returns to the equilibrium position on the surface of the Bloch sphere (---). (After Mao et al )... 

The influence of plant sterols on the phase properties of phospholipid bilayers has been studied by differential scanning calorimetry and X-ray diffraction [206]. It is interesting that the phase transition of dipalmitoylglycerophosphocholine was eliminated by plant sterols at a concentration of about 33 mole%, as found for cholesterol in animal cell membranes. However, less effective modulation of lipid bilayer permeability by plant sterols as compared with cholesterol has been reported. The molecular evolution of biomembranes has received some consideration [207-209]. In his speculation on the evolution of sterols, Bloch [207] has suggested that in the prebiotic atmosphere chemical evolution of the sterol pathway if it did indeed occur, must have stopped at the stage of squalene because of lack of molecular oxygen, an obligatory electron acceptor in the biosynthetic pathway of sterols . Thus, cholesterol is absent from anaerobic bacteria (procaryotes). 

In E. coli, UFAs are generated through the activity of FabA, which anaerobically introduces the double bond into a 10-carbon intermediate formed in the fatty acid biosynthetic pathway (Bloch, 1963, for a recent review see Mansilla et al., 2004). However, other bacteria lacking fab A synthesize UFAs under anoxic conditions. For example, Streptococcus pneumoniae compensates FabA absence with an enzyme called FabM, that is capable of isomerising the trans unsaturated bond of the key 10-carbon intermediate to its cA-isomer (Marrakchi et al., 2002). Nevertheless, FabM seems to be specific for streptococci indicating that there are new anaerobic pathways of UFAs synthesis to be discovered. 

Animals accumulate cholesterol from their diet, but are also able to biosynthesize it from acetate. The pioneering work that identihed the key intermediates in the complicated pathway of cholesterol biosynthesis was carried out by Konrad Bloch (Harvard) and Feodor Lynen (Munich), corecipients of the 1964 Nobel Prize for physiology or medicine. An important discovery was that the triterpene squalene (see Figure 26.6) is an intermediate in the formation of cholesterol from acetate. Thus, the early stages of cholesterol biosynthesis are the same as those of terpene biosynthesis described in Sections 26.8-26.10. In fact, a signihcant fraction of our knowledge of terpene biosynthesis is a direct result of experiments carried out in the area of steroid biosynthesis. 

While PET and iMRI methods allow identification of neural areas activated by respiratory stimuli, these brain-imaging methods cannot discriminate between sensory and motor activation. The pattern of RREP peaks provides neural indicators of the temporal sequence of respiratory sensation. However, RREP studies provide limited information on the specific neural nuclei of the respiratory sensory pathways to the activated discriminative and affective cortices (Bloch-Salisbury and Harver 1994 Bloch-Salisbury et al. 1998 Davenport et al. 1986, 1996 Davenport and Hutchison 2002 Harver et al. 1995 Knafelc and Davenport 1997,1999 Logie et al. 1998 Revelette and Davenport 1990 Webster et al. 2002 Webster and Colrain 2000a, b Zhao et al. 2002). 

The relationship of cholesterol to cholestanol has now been delineated. Early experiments of Schoenheimer ef al. (103, 104) and Rosenfeld and Webster (105) resulted in a proposal that cholesterol was metabolized to -cholestenone (XXIX), which was reduced to cholestanol or coprostanol (106) indeed. Baker and Greenberg (106) detected C-cholestanol in rat feces after administration of radioactive acetate. Anker and Bloch (107) and Stokes et al. (108) found efficient conversion of labeled J -cholestenone to tissue cholestanol in rats. Cholesterol was shown (109) to be a precursor of cholestanol in the adrenals, liver, and intestine of guinea pigs. With cholesterol-4- - C-4/3- H Werbin et al. showed that the cholestanol isolated from the adrenals contained as much as 14% of the tritium at positions 5 and 6, whereas the cholestanol obtained from liver and intestine was virtually devoid of tritium at these positions (110). Based on these observations they proposed the following possible pathway ... 

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