Biosynthesis of CoA from

Figure 1 Biosynthesis of CoA from pantothenic acid. El pantothenate kinase (CoaA) E2 phosphopantothenoylcysteine synthetase (CoaB) ...

Biosynthesis of CoA from pantothenate. Supernatants from livers homogenized in phosphate buffer (pH 7.2,... 

The biosynthesis of CoA from pantothenic acid was markedly increased in liver supernatant after admini-stration of clofibrate. Both by estimating the final product directly, or by the incorporation of pantothenic acid into CoA, rates about 3 fold of normal were found (table 3)-... 

Table 3. Increased biosynthesis of CoA from pantothenic acid in livers from clofibrate-treated rats...

Biosynthesis of CoA from pantothenic acid in the supernatant fraction of the liver. All enzymes required for the biosynthesis of CoA from pantothenic acid have been isolated from the soluble fraction of the cell (8). By using the vitro system of Abiko (cf. 8) for the synthesis of CoA from pantothenic acid, we found the capacity for CoA-biosynthesis to be markedly increased after treatment with clofibrate (2). Dephospho-CoA kinase was not significantly (or only very slightly) increased, but the activity of pantothenate kinase was more than doubled. CoA will exert feed-back inhibition of pantothenate kinase (8), and the extent of this inhibition was not changed by clofibrate (2). 

Biosynthesis of cholesterol from acetyl-CoA proceeds, assisted by the enzymes of endoplasmic reticulum and hyaloplasm, in many tissues and organs. This pro-cess is especially active in the liver of adult humans. 

Figure 3-15. Biosynthesis of stilbene from p-coumaroyl-CoA with three molecules malonyl-CoA, catalyzed by the enzyme stilbene synthase (a E.C. 2.3.1.95).

Fig. 4. X-ray determined protein crystal structures of multienzyme ensembly lines, (a) Mammalian fatty acid synthase at 4.5 A resolution (PDB 2cf2). Domain organization A starter substrate, acetyl-CoA or malonyl-CoA, gets loaded onto the acyl-carrler protein (ACP/absent in the structure) via the malonyl-CoA-/acetyl-CoA-ACP transacylase (MAT). Then, the ketoacyl synthase (KS) catalyzes a decarboxylative condensation reaction and forms the B-ketoacyl-ACP. This is followed from a reduction reaction catalyzed by the B-ketoacyl reductase (KR). Subsequently, the Intermediate gets dehydrated by a dehydratase (DH) and additionally reduced by a B-enoyl reductase (ER). The product gets released from the ACP by a thloesterase (absent in the structure), (b) Module 3 of 6-deoxyerthronolide B synthase at 2.6 A resolution (PDB 2qo3) bound to the inhibitor cerulin. The ketosynthase (KS) - acyltransferase (AT) di-domain is part of the large homodimeric polypeptide involved in biosynthesis of erythromycin from Saccharopolyspora erythraea...

For obvious reasons, inhibitors of cholesterol biosynthesis have aroused intense interest. Studies on a variety of species (mostly rats) have been made using 1-alkylimidazoles," colchicine," and chenodeoxycholic acid, the last work being particularly interesting as the metabolite affected HMG-CoA reductase but not cholesterol 7a-hydroxylase, the steps believed to be rate-limiting for the biosynthesis of sterols and of bile acids respectively. Arsenite, /8-mercaptoethanol, dithiothreitol, and ethanethiol all inhibited the biosynthesis of cholesterol from MVA in rat liver homogenates. The accumulation of 4,4-dimethyl-5a-cholest-8-en-3/3-ol together with the corresponding A -diene supported the view that... 

In the pathway leading to biosynthesis of acetoacetate from acetyl CoA in the liver, the immediate precursor of acetoacetate is which of the following substances ... 

Cobalamin-catalyzed reactions are generally classified into two groups methylcob-alamin-dependent reactions (Table 1, entry 1 to 3) and coenzyme Bi2-dependent rearrangements (Table 1, entry 4 to 11). The first group includes the biosynthesis of methionine from homocysteine, the reduction of CO2 to acetic acid via an acetyl-CoA pathway, and the biosynthesis of CH4 also via an acetyl-CoA pathway. ... 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

Stearoyl-CoA desaturase (SCD) resides in the ER where it catalyzes the biosynthesis of MUFA from SFA that are either synthesized de novo or derived from the diet (Fig. 2). In conjunction with NADH, the flavoprotein cytochrome reductase, the electron acceptor cytochrome b, and molecular oxygen, SCD introduces a single double bond into a spectrum of methylene-intemipted fatty acyl-CoA substrates (Fig. 3). 

Though the reactions in fatty acid biosynthesis resemble the reversal of the analogous reactions in oxidation, fatty acid synthesis is distinct from fatty acid oxidation (Figure 18.23). For example, acyl groups are carried by acyl carrier protein in fatty acid synthesis, instead of coenzyme A. Furthermore, reducing equivalents come from NADPH and energy is provided by ATP. Overall, the biosynthesis of palmitate from 8 acetyl-CoAs requires 7 ATPs and 14 NADPHs. 

In the cellular metabolism F. reacts with citrate synthase to form (2R,3R)-2-fluorocitrate (QH7FO7, Mr 210.12), which inhibits transport of citrate through mitochondrial membranes. The lethal synthesis of fluorocitrate, however, only contributes to a small extent to the toxic activity. D. toxicarium stores F. in its extremely toxic seeds in the form of cu-fluorofatty acids, principally co-fluorooleic acid (C,gH33F02, Mr 300.46). Fluoroacetyl-CoA functions here as a starter unit. The biosynthesis of F. from fluoride ions has not been elucidated. 

A remarkable feature of this synthetic pathway is that the biosynthesis of cholesterol from acetyl-CoA is completely stereoselective cholesterol is synthesized as only one of 256 possible stereoisomers. We cannot duplicate this exquisite degree of stereoselectivity in the laboratory. Cholesterol is, in turn, the key intermediate in the synthesis of all other steroids ... 

Terpenoid metabolism includes terpenoid biosynthesis (from simpler precursor acetyl-CoA to IPP), terpenoidogenesis (the biosynthesis of terpenoids from IPP and the metabolic intercOTversion among diverse terpenoids), and terpenoid degradation (p-oxidatimi pathway). 

Stymne, S. and Appelqvist, L-A. (1978) The biosynthesis of linoleate from oleoyl-CoA via oleoyl-phosphatidylcholine in microsomes of developing safflower seeds, Eur. J. Biochem. 90, 223-229. 

The biosynthesis of CoA in animals requires five enzymes. The first three are foimd only in the cytosol, and the other two are also found in mitochondria. Reaction IV is reversible. Four moles of ATP are required for the biosynthesis of one mole CoA from one mole of pantothenic acid. Two additional enzymes... 

Coenzymes Bjj as cofactors catalyse two completely different types of reactions. Methylcobalamine (as with folacin) acts in some transmethylation reactions (such as biosynthesis of methionine from homocysteine), collaborates with foUc acid in the synthesis of DNA and red blood cells (biosynthesis of porphyrins) and in the fixation of carbon dioxide by some anaerobic acetogennic microorganisms. Enzymes using S -deoxy-S -adenosylcobalamine catalyse a number of isomerisations that are otherwise only viable with difficulty (1,2-rearrangements, such as the formation of succinyl-CoA from methyhnalonyl-CoA) and in some organisms they reduce ribonucleotides to deoxyiibonucleotides. 

Mitochondrial biosynthesis of CoA. We have previously reported that dephospho-CoA kinase is present in mitochondria from liver (2,5,9) and kidney (4). Even though it has been generally thought that the inner mitochondrial membrane is a permeability barrier for CoA (cf. 5), the existence of a separate, mitochondrial pathway for the biosynthesis of CoA has to our knowledge not been suggested. 

The second phase of research [283] has focused on the targeting of the PHA pathway to a specific subcellular compartment, the plastid, where biosynthesis of triglycerides from acetyl-CoA normally occurs. All three genes needed be cloned in this case, and this led to the accumulation of high levels of PHB with few deleterious effects on the growth or fertility of the hosts. The homopolymer was stored within plastids to up to 14% of the dry mass of the plants (a 100-fold increase from expression in the cytoplasm) in the form of granules of size and appearance similar to those of bacterial PHA inclusions. 

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

Whereas catabolism is fundamentally an oxidative process, anabolism is, by its contrasting nature, reductive. The biosynthesis of the complex constituents of the cell begins at the level of intermediates derived from the degradative pathways of catabolism or, less commonly, biosynthesis begins with oxidized substances available in the inanimate environment, such as carbon dioxide. When the hydrocarbon chains of fatty acids are assembled from acetyl-CoA units, activated hydrogens are needed to reduce the carbonyl (C=0) carbon of acetyl-CoA into a —CHg— at every other position along the chain. When glucose is... 

As we began this chapter, we saw that photosynthesis traditionally is equated with the process of COg fixation, that is, the net synthesis of carbohydrate from COg. Indeed, the capacity to perform net accumulation of carbohydrate from COg distinguishes the phototrophic (and autotrophic) organisms from het-erotrophs. Although animals possess enzymes capable of linking COg to organic acceptors, they cannot achieve a net accumulation of organic material by these reactions. For example, fatty acid biosynthesis is primed by covalent attachment of COg to acetyl-CoA to form malonyl-CoA (Chapter 25). Nevertheless, this fixed COg is liberated in the very next reaction, so no net COg incorporation occurs. 

FIGURE 25.31 The biosynthesis of 3/ -tneva-lonate from acetyl-CoA. 

The mevalonate pathway for the biosynthesis of isopentenyl diphosphate from three molecules of acetyl CoA. Individual steps are explained in the text. 

As a rule, the anabolic pathway by which a substance is made is not the reverse of the catabolic pathway by which the same substance is degraded. The two paths must differ in some respects for both to be energetically favorable. Thus, the y3-oxidation pathway for converting fatty acids into acetyl CoA and the biosynthesis of fatty acids from acetyl CoA are related but are not exact opposites. Differences include the identity of the acvl-group carrier, the stereochemistry of the / -hydroxyacyl reaction intermediate, and the identity of the redox coenzyme. FAD is used to introduce a double bond in jS-oxidalion, while NADPH is used to reduce the double bond in fatty-acid biosynthesis. 

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