Metabolic pathways, cyclic

Cyclic nitrosamines are among the most potent and environmentally significant nitrosamine carcinogens. Like the acyclic nitrosamines, metabolism is necessary for their carcinogenicity. Elucidation of the specific metabolic pathways of cyclic nitrosamine activation and detoxification is a challenging problem, and considerable progress has been achieved in recent years. In this chapter, we will review metabolic studies on N-nitrosopyrrolidine (NPYR), N -nitrosonornicotine (NNN), N-nitrosopiperidine (NPIP), N-nitrosohexamethyleneimine (NHEX), N-nitrosomorpholine (NMOR),... 

These studies on NPYR are typical of the state of the art in cyclic nitrosamine metabolism ai d activation. The major metabolic pathways have been rather well characterized, but data on the relationship of these pathways to carcinogenesis are limited. This is especially true of the organospecific effects of NPYR and the other cyclic nitrosamines. For example, the main target organs for NPYR in the Syrian golden hamster are the trachea and nasal cavity rather than the liver. This is in spite... 

Hugueney, P. et ah. Metabolism of cyclic carotenoids a model for the alteration of this biosynthetic pathway in Capsicum annuum chromoplasts. Plant J. 8, 417, 1995. 

We think about metabolic pathways as linear or cyclical sequences of reactions as described in Chapter 1. Individual reactions within a pathway are often dependant upon at least one other reaction. For example, we know from our studies of enzyme kinetics in Chapter 2 that the rate of an enzyme catalysed reaction is determined in part by the concentration of substrate. Remember, the substrate for one reaction is usually the product of a previous reaction, so the activity of an enzyme is affected by the activity of the preceding enzyme in the sequence. 

The tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) is a cyclic metabolic pathway in the mitochondrial matrix (see p. 210). in eight steps, it oxidizes acetyl residues (CH3-CO-) to carbon dioxide (CO2). The reducing equivalents obtained in this process are transferred to NAD"" or ubiquinone, and from there to the respiratory chain (see p. 140). Additional metabolic functions of the cycle are discussed on p. 138. 

FIGURE 4 Three types of nonlinear metabolic pathways (a) Converging, catabolic (b) diverging, anabolic and (c) cyclic, in which one of the starting materials (oxaloacetate in this case) is regenerated and reenters the pathway. Acetate, a key metabolic intermediate, is... 

The biosynthetic studies undertaken to date on microbial marine natural products well illustrate the diversity of metabolic pathways encountered in cultured marine bacteria. Examples include brominated alkaloids such as pentabromopseudiline (Structure 2.1),19 polyketide or mixed polyketide metabolites such as oncorhyncholide (Structure 2.2),20 aplasmomycin (Structure 2.3),21 and andrimid (Structure 2.4),22 or the cyclic depsipeptide salinamide A (Structure 2.5).23 As researchers continue to define more specific culture media and a wider range of marine bacteria from diverse habitats are successfully placed into culture, the true biosynthetic potential of these prolific and adaptable microorganisms can be explored. 

The urea cycle Urea is synthesized in the liver by the urea cycle. It is then secreted into the bloodstream and taken up by the kidneys for excretion in the urine. The urea cycle was the first cyclic metabolic pathway to be discovered by Hans Krebs and Kurt Henseleit in 1932,5 years before Krebs discovered the citric acid cycle (see Topic LI). The overall reaction of the pathway is ... 

Some metabolic pathways are linear, some are cyclic, and some are branched, yielding multiple end products from a single precursor or converting several precursors into a single product. 

In addition to the stimulatory actions of LH and hCG on steroidogenesis in Leydig cells and ovarian cells, these hormones also cause a refractoriness or desensitization of that same steroidogenic response. This may involve a loss of LH receptors (down regulation), an uncoupling of the LH receptor from the adenylate cyclase, an increase in the metabolism of cyclic AMP due to an increased phosphodiesterase activity and a decrease in the activities in some of the enzymes in the pathways of steroidogenesis (see Ref. 69 for other references). 

In terrestrial vertebrates, urea is synthesized by the urea cycle (Figure 23.16). The urea cycle, proposed by Hans Krebs and Kurt Henseleit in 1932, was the first cyclic metabolic pathway to be discovered. One of the nitrogen atoms of the urea is transferred from an amino acid, aspartate. The other nitrogen atom is derived directly from free NH4 +, and the carbon atom comes from HCO3 (derived by hydration of CO2 see Section 9.2). 

Most such metabolic pathways are linear, that is, they begin with a specific substrate and end with a specific product. However, some pathways, such as the Krebs cycle, are cyclic. Often, metabolic pathways also have branches that feed into or out of them. The specific sequences of intermediates in the pathways of cell metabolism are called intermediary metabolism. 

A cyclic metabolic pathway in which amino groups are converted to urea... 

Recent studies identify a new metabolic pathway for chloropicrin involving a rapid dechlorination to CHCI2NO2 and conversion of glutathione (GSH) to GSSG plus possible adduct formation with thiol proteins. In this newly discovered pathway, chloropicrin is metabolized to thiophosgene, characterized as the cyclic cysteine adduct (raphanusamic acid) in mice urine. The initially formed GS-CCI2NO2 metabolite is proposed to either react further with GSH or is cleaved by cysteine-/l-lyase, ultimately leading to raphanusamic acid, which is excreted. Chloropicrin is an... 

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