Coenzyme in intermediary metabolism

Nicotinic acid and nicotinamide are precursors of the coenzymes NAD+ and NADP+, which play a vital role in oxidation-reduction reactions (see Box 7.6), and are the most important electron carriers in intermediary metabolism (see Section 15.1.1). We shall look further at the chemistry of NAD+ and NADP+ shortly (see Box 11.2), but note that, in these compounds, nicotinamide is bound to the rest of the molecule as an A-pyridinium salt. 

Because flavin coenzymes are widely distributed in intermediary metabolism, the consequences of deficiency maybe widespread. Because riboflavin coenzymes are involved in the metabohsm of folic acid, pyridoxine, vitamin K, and niacin, deficiency will affect enzyme systems other than those requiring flavin coenzymes. With increasing riboflavin deficiency, tissue concentrations of FMN and FAD fall, as does flavokinase activity, thus further decreasing FMN concentrations. FMN concentrations are decreased proportionally more than FAD concentrations. Decreases in the activities of enzymes requiring FMN generally follow the fall in tissue concentrations, whereas the FAD-dependent enzymes are more variably affected. ... 

He also was the first to recognize its importance in intermediary metabolism. Lipmann was bom in Germany. To escape the Nazis, he moved to Denmark in 1932 and to the United States in 1939, becoming a U.S. citizen in 1944. For his work on coenzyme A, he received the Nobel Prize in physiology or medicine in 1953, sharing it with Hans Krebs. 

In 1948, Lipmann and his coworkers established the structure and the role of coenzyme A in its conversion to acetyl CoA (see the structure below), noting that the thioacetate linkage (-S-COCH3) is a high-energy linkage like the pyrophosphate linkage in ATP. The presence of pantothenic acid, one of the B vitamins, in the structure of coenzyme A (see the structure) explains its vital role in intermediary metabolism. For these... 

With the development of knowledge concerning the role of pantothenic acid in intermediary metabolism, the critical importance of this vitamin to adrenocortical function becomes more understandable. When the adrenal cortex is stimulated by stressful situations, its function is to respond rapidly by secreting steroid hormones which initiate and maintain a variety of physiological reactions. Its ability to synthesize these hormones may depend on its capacity to mobilize energy rapidly. Pantothenic acid, as part of coenzyme A, plays a critical role in the oxidative metabolism of both carbohydrate and fatty acids and may also be involved directly in lipid synthesis. Therefore, a deficiency in pantothenic acid can create a situation in which the ability of the adrenocortical cells to secrete steroid hormones is seriously impaired. 

Experiments of this type are subject to several intrinsic difficulties which Winters discusses in some detail. Adrenal function can be assayed by physiological responses of this type only if the tissue on which the adrenal hormone acts is functioning normally. Owing to the critical role of coenzyme A in intermediary metabolism, the maintenance of normal function in any tissue during severe pantothenate deficiency is doubtful. However, experiments attempting to define adrenocortical function by studies of carbohydrate metabolism in situations of severe pantothenate deficiency are partially justified by the finding of Olson and Kaplan (1948) that in the rat the adrenal cortex suffers an earlier depletion of coenzyme A than does the liver. After 3 weeks of pantothenate deficiency, coenzyme A was significantly decreased in the adrenal and heart, whereas it was still at normal levels in the liver and kidney. After 6 weeks on the... 

The exact role of the adrenocortical hormones in intermediary metabolism is still amost completely obscure. Hormones may exert their effects through their influence on the rates of enzymatic reactions. If such enzymatic reactions also require some nutritional factor as part of a coenzyme, altered nutritional requirements as a consequence of changes in hormone levels might be anticipated. 

The purine nucleotides GTP and ATP are very important in intermediary metabolism and the regulation of metabolism. Adenine is also a component of cyclic AMP, FAD, NAD, NADP and coenzyme A. Moreover, GTP, ATP and their deoxy derivatives dGTP and dATP are important precursors for the synthesis of RNA and DNA respectively, which are essential for cell growth and division. Purine biosynthesis (Fig. 59.1) needs the amino acids giutamine, giycine and aspartate. Also, tryptophan is needed to supply formate which reacts with tet-rahydrofolate (THF) to produce A "-formyl THF, which donates the formyl group to the purine structure. A molecule of CO2 is also needed. 

Deficiency of riboflavin leads to a variety of clinical abnormalities that include neurological disorders, anaemia, growth retardation and skin abnormalities. Moreover, inadequate intakes of riboflavin lead to disturbances in intermediary metabolism. Severe riboflavin deficiency can also affect the conversion of vitamin Bs to its coenzyme and even decrease conversion of tryptophan to niacin. Recently, Nakano et al. (2011) demonstrated that riboflavin deficiency in humans results in altered cell turnover in the duodenal crypt. 

Mammals cannot synthesize biotin and depend on a regular dietary supply of this water-soluble vitamin (Zempleni et al., 2009). The Adequate Intake for biotin in adults is 30 pg/d (National Research Council, 1998). The classical role of biotin in mammalian intermediary metabolism is to serve as a covalently bound coenzyme in five carboxylases (Zanpleni et al., 2D09). Both the cytoplasmic acetyl-CoA carboxylase 1 (ACCl) and the mitochondrial acetyl-CoA carboxylase 2 (ACC2) catalyze the binding of bicarbonate to acetyl-CoA to generate malonyl-CoA, but the two isoforms have distinct functions in intermediary metabolism (Kim et al., 1997). ACCl produces malonyl-CoA for the synthesis of fatty acid synthesis in the cytoplasm ACC2... 

The archaebacteria differ from eubacteria in that they lack muramic acid and therefore a peptidoglycan cell wall [6,7], their membrane lipids are based on ether linkages, rather than ester linkages [8-11] and they differ in intermediary metabolism and coenzyme complement [12,13]. The differences between archaebacteria and eubacteria imply that the former are a source of unique enzymes, but so far only a few of these have been studied (see below). 

A member of the water-soluble B group of vitamins. It can be obtained from thediet orit can be synthesized endogenouslyfrom nicotinic acid, which is itself derived from tryptophan. Nicotinamide is a constituent of the coenzymes NAD and N ADP which have widespread roles in intermediary metabolism. Deficiency of the vitamins causes pellagra. Patients with Hart-nup s disease can develop a pellagra type condition probably due to insufficient endogenous synthesis of the vitamin from tryptophan. 

A water-soluble vitamin of the B group. It is a component of coenzyme A which participates in many reactions in intermediary metabolism. 

Mechanism of toxicolo damage. Fluoroacetate aixl fluoroacetamide replace acetyl-coenzyme A in intermediary metabolism and combine with oxaloao ic add to form fluoraotrate. 

The participation of thiol esters in intermediary metabolism became widely recognized since the discovery of coenzyme A, and is discussed in a separate chapter. S-Acetylglutathione ISO, ISl) is rapidly decomposed by liver extracts. The thiolesterase responsible for this reaction has been purified by Kielley and Bradley 1S2). 

The intermediary metabolism has multienzyme complexes which, in a complex reaction, catalyze the oxidative decarboxylation of 2-oxoacids and the transfer to coenzyme A of the acyl residue produced. NAD" acts as the electron acceptor. In addition, thiamine diphosphate, lipoamide, and FAD are also involved in the reaction. The oxoacid dehydrogenases include a) the pyruvate dehydrogenase complex (PDH, pyruvate acetyl CoA), b) the 2-oxoglutarate dehydrogenase complex of the tricarboxylic acid cycle (ODH, 2-oxoglutarate succinyl CoA), and c) the branched chain dehydrogenase complex, which is involved in the catabolism of valine, leucine, and isoleucine (see p. 414). 

As the principal thiolester of intermediary metabolism, acetyl coenzyme A is involved in two-carbon biosynthetic and degradative steps. An essential component is the vitamin pantithenic acid, which provides the sulfur atom for the thiolester formation. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

The literature concerning malo—lactic fermentation—bacterial conversion of L-malic acid to L-lactic acid and carbon dioxide in wine—is reviewed, and the current concept of its mechanism is presented. The previously accepted mechanism of this reaction was proposed from work performed a number of years ago subsequently, several workers have presented data which tend to discount it. Currently, it is believed that during malo-lactic fermentation, the major portion of malic acid is directly decarboxylated to lactic acid while a small amount of pyruvic acid (and reduced coenzyme) is formed as an end product, rather than as an intermediate. It is suspected that this small amount of pyruvic acid has extremely important consequences on the intermediary metabolism of the bacteria. 

Additionally it should be remembered that nicotine metabolites still retain a pyridyl moiety and this functional group can release nicotinamide from NADPH and generate an analogue of the coenzyme via a glycohydrolase. As these analogues may not be able to participate in the normal oxido/reduction reactions of intermediary metabolism certain pathways may be inhibited leading to accumulation of substrates e.g. glucose-6-phosphate and diminution of availability of products e.g. ribose, and thereby affect purine, pyrimidine and nucleic acid biosynthesis. 

Amide bonds are found in many proteins. One is the acyl carrier protein of Escherichia coli (see 90), which contains the peptide backbone, and a 4 -phosphopantetheine unit (in violet in the illustration) is attached to a serine residue. Note the amine bonds in the pantothenic acid unit and also the 0-P=0 unit, which is a phosphate ester (an ester of phosphoric acid). An acyl carrier protein is involved in fatty acid synthesis, linking acetyl and malonyl groups from acetyl coenzyme A and malonyl coenzyme A to form P-keto acid acyl carrier protein (abbreviated as ACP). The widely utilized acetyl CoA is an ester (91) attached to coenzyme A. Acetyl CoA is a key intermediate in aerobic intermediary metabolism of carbohydrates, lipids, and some amino acids. 

Apart from AT-oxidation, most of the above reactions require a special cytochrome coenzyme known as (because it absorbs visible light intensely at 450 nm), also the coenzyme NADP, and a fiavoprotein enzyme (cytochrome c reductase) which utilizes the oxygen of air (Gillette, 1966). These e,r, enzymes, by their requirement for NADP, stand apart from the many NAD-requiring enzymes that the body s intermediary metabolism uses in its stepwise conversions of nutriment into energy. Conversely, the e,r, enzymes attack neither the raw materials nor the products of intermediary metabolism, partly because such substances are too hydrophilic to penetrate into the e.r. 

An intermediate enzyme-coenzyme A complex in which the energy of the thioester bond is preserved has been demonstrated. Here the coenzyme A thioester is involved in a transfer reaction quite different from its usual acyl donor role. Functionally this enzyme allows metabolically generated coenzyme A derivatives to be utilized directly for carboxylic acid activation, without intermediary formation of nudeoside triphosphates. 

Higher alcohol production by yeasts appears to be linked not only to the catabolism of amino acids but also to their synthesis via the corresponding ketonic acids. These acids are derived from the metabolism of sugars. For example, propan-l-ol has no corresponding amino acid. It is derived from a-ketobutyrate which can be formed from pyruvate and acetyl coenzyme A. a-Ketoisocaproate is a precursor of isoamylic alcohol and an intermediary product in the synthesis of leucine. It too can be produced from a-acetolactate, which is derived from pyruvate. Most higher alcohols in wine can also be formed by the metabolism of glucose without the involvement of amino acids. 

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