Catabolism lyases

Pyruvate-dependent lyases serve catabolic functions in vivo in the degradation of sialic acids and KDO (2-keto-3-deoxy-manno-octosonate), and in that of 2-keto-3-deoxy aldonic acid intermediates from hexose or pentose catabolism. 

Erwinia chrysanthemi synthesizes and secretes a large number of pectinases. The major pectinases include a pectin methylesterase PemA and five isoenzymes of endo-pectate lyases PelA, PelB, PelC, PelD and PelE. In addition, secondary pectinases were identified a pectin methylesterase PemB, two endo-pectate lyases PelL and PelZ, an exo-pectate lyase PelX and an exopolygalacturonase, PehX. The regulation of pectinase synthesis is very complex and dependent on many environmental conditions. It is induced by pectin catabolic products and affected by growth phase, catabolite repression, osmolarity, iron or oxygen starvation... 

Three regulators were identified by genetic analysis. The main repressor, KdgR, controls the transcription of pectinase genes, the intracellular catabolic pathway and the secretion machinery. The PecS repressor controls the production of pectate lyases and cellulases, the secretion machinery and the biosynthesis of a blue pigment. PecT acts as a repressor of the production of some pectate lyases. Other proteins are involved in the regulation of pectinase s5mthesis but their role is not well characterized. 

More recently, Pearce and Heydeman suggested non-oxidative removal of ethylene glycol units as acetaldehyde by a membrane-bound, oxygen-sensitive enzyme of a novel type, i.e., diethylene glycol lyase (18). Schoberl suggested that PEG was catabolized by Ci step, liberating formate which was metabolized by a serine pathway (19). 

Catabolism Utilizing Tissue C-S Lyases And Microfloral S-Glucuronidases In Addition To The Microfloral C-S Lyase... 

Akhmanova A, Voncken FGJ, Hosea KM, Harhangi H, Keltjens JT, den Camp HJMO, Vogels GD, Hackstein JHP (1999) A hydrogenosome with pyruvate formate-lyase anaerobic chytrid fungi use an alternative route for pyruvate catabolism. Mol Microbiol 32 1103-1114... 

Hexachlorobutadiene is a nephrotoxic industrial chemical, damaging the pars recta of the proximal tubule. Initial conjugation with GSH is necessary, followed by biliary secretion and catabolism resulting in a cysteine conjugate. The conjugate is reabsorbed and transported to the kidney where it can be concentrated and becomes a substrate for the enzyme p-lyase. This metabolizes it into a reactive thiol, which may react with proteins and other critical macro molecules with mitochondria as the ultimate target. The kidney is sensitive because the metabolite is concentrated by active uptake processes (e.g., OAT 1), which reabsorb the metabolite into the tubular cells. 

FIGURE 18-26 Catabolic pathways for arginine, histidine, glutamate, glutamine, and proline. These amino acids are converted to a-ketoglutarate. The numbered steps in the histidine pathway are catalyzed by histidine ammonia lyase, urocanate hydratase, imida-zolonepropionase, and glutamate formimino transferase. 

A very similar reaction is catalyzed by 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase), which functions in the formation of acetoacetate in the human body (Eq. 17-5, step c) and also in the catabolism of leucine (Fig. 24-18)182183 and in the synthesis of 3-hydroxy-3-methyIgIutaryI-CoA, the presursor of cholesterol (Eq. 17-5, step fr)183a... 

Catabolism of histidine in most organisms proceeds via an initial elimination of NH3 to form urocanic acid (Eq. 14-44). The absence of the enzyme L-histidine ammonia-lyase (histidase) causes the genetic disease histidinemia 284/285 A similar reaction is catalyzed by the important plant enzyme L-phenylalanine ammonia-lyase. It eliminates -NH3+ along with the pro-S hydrogen in the (3 position of phenylalanine to form frans-cinnamate (Eq. 14-45). Tyrosine is converted to p-coumarate by the same enzyme. Cinnamate and coumarate are formed in higher plants and are converted into a vast array of derivatives (Box 21-E,... 

In vivo, pyruvate lyases perform a catabolic function. The synthetically most interesting types are those involved in the degradation of sialic acids or the structurally related octulosonic acid KDO, which are higher sugars typically found in mammalian or bacterial glycoconjugates [62-64], respectively. Also, hexose or pentose catabolism may proceed via pyruvate cleavage from intermediate 2-keto-3-deoxy derivatives which result from dehydration of the corresponding aldonic acids. Since these aldol additions are freely reversible, the often unfavourable equilibrium constants require that reactions in the direction of synthesis have to be driven by an excess of one of the components, preferably pyruvate for economic reasons, in order to achieve a satisfactory conversion. 

Free amino acids are further catabolized into several volatile flavor compounds. However, the pathways involved are not fully known. A detailed summary of the various studies on the role of the catabolism of amino acids in cheese flavor development was published by Curtin and McSweeney (2004). Two major pathways have been suggested (1) aminotransferase or lyase activity and (2) deamination or decarboxylation. Aminotransferase activity results in the formation of a-ketoacids and glutamic acid. The a-ketoacids are further degraded to flavor compounds such as hydroxy acids, aldehydes, and carboxylic acids. a-Ketoacids from methionine, branched-chain amino acids (leucine, isoleucine, and valine), or aromatic amino acids (phenylalanine, tyrosine, and tryptophan) serve as the precursors to volatile flavor compounds (Yvon and Rijnen, 2001). Volatile sulfur compounds are primarily formed from methionine. Methanethiol, which at low concentrations, contributes to the characteristic flavor of Cheddar cheese, is formed from the catabolism of methionine (Curtin and McSweeney, 2004 Weimer et al., 1999). Furthermore, bacterial lyases also metabolize methionine to a-ketobutyrate, methanethiol, and ammonia (Tanaka et al., 1985). On catabolism by aminotransferase, aromatic amino acids yield volatile flavor compounds such as benzalde-hyde, phenylacetate, phenylethanol, phenyllactate, etc. Deamination reactions also result in a-ketoacids and ammonia, which add to the flavor of... 

Glutamine transaminase from bovine liver, one of the enzymes involved in methionine catabolism, utilizes SeMet as well as methionine (Blazon et al., 1994). However, with some enzymes, differences in the reaction rates for SeMet and Met have been observed. For example, SeMet is a better substrate than Met for the a,7-elimination by L-methionine 7-lyase of Pseudomonas putida (Esaki et al., 1979). The adenosyltransferase from rat liver reacts with L(+)-SeMet at 51% of the rate with L(+)-Met, and with the corresponding d(—) isomers at only 13 and 10% of the rate of L-Met (Pan and Tarver, 1967). The adenosyl transferase from yeast, on the other hand, is more active with SeMet than with Met (Mudd and Cantoni, 1957). This enzyme produces the... 

HMG-CoA lyase is normally present in the mitochondrial matrix.To understand the complexity of the metabolic problems of a patient with HMG-CoA lyase deficiency, it is necessary to consider the role of this enzyme in two very distinct metabolic pathways catabolism of leucine and ketogenesis. 

Figure 20-3. Pathway for the catabolism of leucine. The last step in the pathway is catalyzed by 3-hydroxy-3methyl-CoA lyase, which is deficient in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.

Individuals who are deficient in HMG-CoA lyase are unable to complete the metabolism of leucine. The increased urinary excretion of 3-hydroxy-3-methylglutaric acids is the primary biochemical criterion that distinguishes this particular enzymatic defect from other defects in enzymes of leucine catabolism that also result in metabolic acidosis and abnormal organic aciduria. There is also substantial urinary excretion of intermediates of leucine catabolism, such as 3-methylglutaconic acid, and their metabolites, including 3-hydroxy-isovaleric acid produced from isovaleric acid. 

Individuals with HMG-CoA lyase deficiency are particularly susceptible to carnitine deficiency. With restriction of red meats and dairy products, dietary carnitine intake is quite low. Carnitine is also synthesized endogenously from the modified, methylated lysine resides of various proteins free trimethyllysine is released when the protein is degraded. Since the therapy for patients with HMG-CoA lyase deficiency must minimize their endogenous protein catabolism, they also have limited availability of trimethyllysine for carnitine synthesis. 

Nutritional therapy for HMG-CoA lyase deficiency has two major goals. First, the prescribed diet aims to provide enough total protein and calories to achieve normal growth and maintain metabolic balance in the context of a leucine-restricted diet. Equally important, the nutritional therapy focuses on preventing excess catabolism, acidosis, and hypoglycemia, especially during times of acute illness. For these patients, it is particularly important to avoid fasting at any time. 

In summary, HMG-CoA lyase deficiency is a unique inborn error of metabolism with profound effects on both amino acid catabolism and metabolic homeostasis in the fasted state. Management of these patients is difficult and requires constant attention to daily nutrition and timely intervention during acute illness. Fortunately, nutritional therapy treatment that provides a diet adequate for growth but with limited intake of leucine and prevents fasting and hypoglycemia enables individuals with HMG-CoA lyase deficiency to live normal active lives. 

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