First committed step

The entire biosynthesis pathway of artemisinin has not been elucidated yet. The first committed step is conversion of FPP to amorphadiene via the cyclization catalyzed by ADS [102] followed by further oxidations of amorphadiene to artemisinic acid. Artemisinic acid can be used as a precursor for semi-synthesis of artemisinin and related chemicals [88]. 

Acetyl-CoA carboxylase (ACCase) carboxylates acetyl-CoA into malo-nyl-CoA and therefore represents the first committed step in fatty acid biosynthesis. ACCase is a multimer essential for cell growth whose components are highly conserved among bacteria, making it a promising broad-spectrum target [8]. 

The six-membered aromatic A ring originates from three units of malonyl-CoA, produced from citrate precursors through the activity of a cytosolic acetyl-CoA carboxylase (ACC) (Fatland and others 2004) (see Fig. 5.1). These three malonyl-CoA units are added through sequential decarboxylation condensation reactions and actually represent the first committed step toward flavonoid biosynthesis. 

COXs thus catalyze the same first committed step of the AA cascade (Fig. 33-2). COX-2, however, is expressed in response to mitogenic and inflammatory stimuli and encoded by an early-response gene. To date we do not understand how COX-3 expression is regulated. In contrast, COX-1 expression is not subject to short-term regulation. Neurons in the hippocampus, as well as in a few other brain regions, are unlike other cells in that they display basal COX-2 expression [36]. This expression is modulated by synaptic activity, such as long-term potentiation, and involves the NMDA glutamate receptors [36,40]. 

CYCLIZATION OF 2,3-OXIDOSQUALENE - THE FIRST COMMITTED STEP IN TRITERPENOID BIOSYNTHESIS... 

Triterpenoid saponins are synthesized via the isoprenoid pathway.4 The first committed step in triterpenoid saponin biosynthesis involves the cyclization of 2,3-oxidosqualene to one of a number of different potential products (Fig. 5.1).4,8 Most plant triterpenoid saponins are derived from oleanane or dammarane skeletons although lupanes are also common 4 This cyclization event forms a branchpoint with the sterol biosynthetic pathway in which 2,3-oxidosqualene is cyclized to cycloartenol in plants, or to lanosterol in animals and fungi. 

Acetyl-CoA carboxylase (ACC) catalyses the ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA, the rate limiting, first committed step in fatty... 

As the first committed step in the biosynthesis of AMP from IMP, AMPSase plays a central role in de novo purine nucleotide biosynthesis. A 6-phosphoryl-IMP intermediate appears to be formed during catalysis, and kinetic studies of E. coli AMPSase demonstrated that the substrates bind to the enzyme active sites randomly. With mammalian AMPSase, aspartate exhibits preferred binding to the E GTPTMP complex rather than to the free enzyme. Other kinetic data support the inference that Mg-aspartate complex formation occurs within the adenylosuccinate synthetase active site and that such a... 

The prototypical allosteric regulatory protein isolated from Escherichia coli (molecular weight 310,000). The enzyme [EC 2.1.3.2], also known as aspartate transcarba-mylase and carbamylaspartotranskinase, catalyzes the first committed step i.e., the transfer of a carbamoyl... 

The final product(s) generated by a sequence of enzyme-catalyzed steps within a metabolic pathway. End products frequently act as potent inhibitors of the first commited step in a metabolic pathway leading to their synthesis. End products are also known to accelerate the rate of another metabolic pathway leading to a different set of end products. The highly coordinated biosynthesis of adenine and guanine nucleotides provides examples of negative and positive effects of end products of each pathway. 

Cyclization of 2,3-Oxidosqualene - The First Committed Step in Triterpenoid Biosynthesis... 

Carotenoids produced in plants are used as colorants in foods and aiflmal feeds and can also have an antioxidant function. Production of phytoene synthase is the first committed step towards carotenoid biosynthesis in plants. When phytoene synthase is produced in B. napus, a 50-fold increase in carotenoid expression results. Therefore Brassica... 

This enzyme is called PFK-1 to distinguish it from a second enzyme (PFK-2) that catalyzes the formation of fructose 2,6-bisphosphate from fructose 6-phosphate in a separate pathway. The PFK-1 reaction is essentially irreversible under cellular conditions, and it is the first committed step in the glycolytic pathway glucose 6-phosphate and fructose 6-phosphate have other possible fates, but fructose 1,6-bisphosphate is targeted for glycolysis. 

In the first committed step of the pathway an amino group donated by glutamine is attached at C-l of PRPP (Fig. 22-33). The resulting 5-phosphoribosylamine is highly unstable, with a half-life of 30 seconds at pH 7.5. The purine ring is subsequently built up on this structure. The pathway described here is identical in all organisms, with the exception of one step that differs in higher eukaryotes as noted below. 

Bacterial RNA polymerase requires a special subunit to recognize the promoter. As the first committed step in transcription, binding of RNA polymerase to the promoter and initiation of transcription are closely regulated. Transcription stops at sequences called terminators. 

Many lines of evidence indicate that the first committed step in de novo purine nucleotide biosynthesis, production of 5-phosphoribosylamine by glutamine PRPP amidotransfer-ase, is rate-limiting for the entire sequence. Consequently, regulation of this enzyme is probably the most important factor in control of purine synthesis de novo (fig. 23.24). The enzyme is inhibited by purine-5 -nucleotides, but the most inhibitory nucleotides vary with the source of the enzyme. Inhibition constants (A, ) are usually in the range 10-3-10-5 M. The maximum effect of this end-product inhibition is produced by certain combinations of nucleotides (e.g., AMP and GMP) in optimum concentrations and ratios, indicating two kinds of inhibitor binding sites. This is an example of a concerted feedback inhibition. 

In bacteria, the first committed step in pyrimidine nucleotide biosynthesis is the formation of carbamoyl aspartate... 

The irreversible condensation reaction between a starter hydroxycinnamoyl-CoA molecule and three acetate extender units derived from malonyl-CoA constitute the first committed step of flavonoid and stilbene biosynthesis [Springob et al., 2003] (Fig. 21.2). The reactions catalyzed by two type III... 

HMG-CoA reductase mediates the first committed step in sterol biosynthesis. The active forms of the reductase inhibitors are structural analogs of the HMG-CoA intermediate (Figure 35-3) that is formed by HMG-CoA reductase in the synthesis of mevalonate. These analogs cause partial inhibition of the enzyme and thus may impair the synthesis of isoprenoids such as ubiquinone and dolichol and the prenylation of proteins. It is not known whether this has biologic significance. 

As many metabolic pathways are branched, feedback inhibition must allow the synthesis of one product of a branched pathway to proceed even when another is present in excess. Here a process of sequential feedback inhibition may operate where the end-product of one branch of a pathway will inhibit the first enzyme after the branchpoint (the conversion of C to D or C to E in Fig. lb). When this branchpoint intermediate builds up, it in turn inhibits the first committed step of the whole pathway (conversion of A to B in Fig. lb). Since the end-product of a metabolic pathway involving multiple enzyme reactions is unlikely to resemble the starting compound structurally, the end-product will bind to the enzyme at the control point at a site other than the active site. Such enzymes are always allosteric enzymes. 

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