Cyclic Metabolism

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. 

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 ... 

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). 

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

A simple way to avoid the disruption of label coherence by cyclic metabolic processes is the use of complex precursors from a relatively late stage of a biosynthetic pathway under study. However, this approach is subject to other limitations such as the failure to make the correct guess with regard to the structure of precursors, the failure of correctly guessed precursors to reach the intracellular site of the biosynthetic process under study,or the impossibility of preparing or otherwise obtaining a multilabeled specimen at an acceptable price and/or effort. 

In the development of the nervous system of vertebrates Kluver (187) found a progressive upward deposition of coporporphyrin in the white matter beginning in the spinal cord and extending into the bnun. Certain cranial nerves like the optic were found to contain more porphyrin and others like the auditory lacked it. These observationa are of interest in connection with the cyclic metabolic chaises apparently induced by light in various species of birds and mammals. 

FIGURE 3.1 Basic principles of metabolism. The unit of metabolism is the chemical reaction, catalyzed by an enzyme (upper left). Each reaction can be studied individually in vitro to determine its mechanism and kinetics parameters. In a linear metabolic pathway (e.g., glycolysis), the reactions are coupied in series (lower left). The rate of the first reaction of the chain (A + B C) reaction is controlled by the fluxes of A and B. The flux through the whole metabolic pathway is determined by the rate of production of E. The same rules apply for a cyclic metabolic pathway such as Krebs cycle (right panel). 

Intracellular degradation of PHA by depolymerases has not been studied in as much depth as compared to extracellular PHA degradation. C. necator, an organism able to accumulate PHB, was the organism of research to study the intracellular mobilization. This is mediated by a cyclic metabolic route from... 

Krebs, (Sir) Hans Adolf (1900-81) German-born British biochemist renowned for his work on metabolism and, in particular, for the discovery of the cyclic metabolic pathways named after him. He was awarded the Nobel Prize for physiology or medicine in 1953 for his discovery of the TCA cycle. The prize was shared with F. A. Lipmann. 

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

Isomers of D-apiofuranosyl 1-phosphate have been prepared by treating a mixture of jS-o-apio-D-furanosyl and /3-D-apio-L-furanosyl tetra-acetates with crystalline phosphoric acid. a-o-Apio-o- (59) and a-o-apio-L-furanosyl-1-phosphate (60) and their cyclic phosphates were separated by chromatography and identified by H n.m.r. o-Apiose is metabolized in parsley and Lemna minor with the possible formation of UDP-D-apiose. L. minor will convert UDP-a-glucuronic acid into a-o-apio-D-furanosyl-1,2-cyclic phosphate (61) but no evidence of UDP-o-apiose was found, although it is possible that (61) arose from the rapid hydrolysis of UDP-o-apiose. 

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),... 

The metabolism of NPYR is summarized in Figure 1. a-Hy-droxylation (2 or 5.position) leads to the unstable intermediates and decomposition of gives 4-hydroxybutyraldehyde [ ]. The latter, which exists predominantly as the cyclic hemiacetal 1, has been detected as a hepatic microsomal metabolite in rats, hamsters, and humans and from lung microsomes in rats (9-13). The role of 1 and as intermediates in the formation of 6 and 7 is supported by studies of the hydrolysis of 2-acetoxyNPYR and 4-(N-carbethoxy-N-nitrosamino)butanal, which both gave high yields of 7 (9,14). In microsomal incubations, can be readily quantified as its 2,4-dinitrophenylhydrazone derivative (15). The latter has also been detected in the urine of rats treated with NPYR ( ). 

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