Regulatory site

In animals, acetyl-CoA carboxylase (ACC) is a filamentous polymer (4 to 8 X 10 D) composed of 230-kD protomers. Each of these subunits contains the biotin carboxyl carrier moiety, biotin carboxylase, and transcarboxylase activities, as well as allosteric regulatory sites. Animal ACC is thus a multifunctional protein. The polymeric form is active, but the 230-kD protomers are inactive. The activity of ACC is thus dependent upon the position of the equilibrium between these two forms ... 

In die metabolic pathway to an amino add several steps are involved. Each step is die result of an enzymatic activity. The key enzymatic activity (usually die first enzyme in the synthesis) is regulated by one of its products (usually die end product, eg die amino add). If die concentration of die amino add is too high die enzymatic activity is decreased by interaction of die inhibitor with the regulatory site of die enzyme (allosteric enzyme). This phenomenon is called feedback inhibition. 

The site level at which [Ca2+]i regulates NCX activity (CBD) is different from the one required for Ca2+ transport. Submicromolar concentrations (0.1-0.3 pM) of intracellular Ca2+ are needed to activate the antiporter through these Ca2+ binding site. The location of such regulatory site has been identified in the 134-amino acid-length region, situated in the center of the intracellular f loop [2], (Table 1)... 

Johnson, J.D., Collins, J.H., and Potter, J.D. (1978) Dansylaziridine labeled troponin C. A fluorescent probe of calcium ion binding to the calcium ion-specific regulatory sites./. Biol. Chem. 253, 6451. 

HDC activity can be regulated by both hormonal and neuronal factors, most of which are poorly understood. Phosphorylation of the enzyme by PKA maybe an important regulatory mechanism. Several regulatory sites have recently been found in the promoter region of the gene. 

V-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites 276... 

V-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites. To date, three NMDA receptor subunit families have been identified, one represented by a single gene (NR1, encoding a protein of -900 amino acids), the... 

The regions outside the catalytic domain, particularly the amino terminus, are much more variable across the different PDE families. These regions contain many of the regulatory sites that control PDE activity (Fig. 21-6). For example, this region contains the Ca27calmodulin... 

FIGURE 21-6 Schematic illustration of the overall structure and regulatory sites of eleven different phosphodiesterase subtypes. The catalytic domain of the phosphodiesterases are relatively conserved, and the preferred substrate(s) for each type is shown. The regulatory domains are more variable and contain the sites for binding of Ca2+/calmodulin (CaM) and cGMP, as well as GAF and PAS domains. The regulatory domains also contain sites of phosphorylation by cAMP-dependent protein kinase (PKA). 

Ligand-bound corticosteroid receptors have been shown to interact to form heterodimers with other transcription factors, such as the jun protein. Such interactions are responsible for transactivation of the ds-regulatory sites known as AP-1 sites and for the glucocorticoid-mediated suppression of transcription, such as that seen in the pro-opiomelanocortin gene. A number of such specific protein interactions have been reported these interactions and their locations relative to other transcription factors transform a ubiquitous steroid hormone signal into a tissue-specific, graded cellular response. 

The regulation of free intracellular Ca2+ is a complex, multi-faceted process (see Chs. 5 and 22), and the abnormalities observed in bipolar disorder could arise from abnormalities at a variety of levels. Ongoing studies should serve to delineate the specific regulatory sites at which the impairment occurs in bipolar disorder. 

G-CSF expression is controlled at both the transcriptional and posttranscrip-tional levels. A sequence of 300 nucleotides upstream of the initiation codon is conserved in both the murine and human genes, and this appears to contain three regulatory sites. G-CSF (and some other cytokine genes) may be constitutively transcribed by cells such as blood monocytes, fibroblasts and endothelial cells, but the mRNA may be short-lived (fi/2 < 15 min). The mRNA contains poly-AUUUA sequences in the untranslated region, and this motif is usually associated with mRNA instability. Indeed, such regions have also been identified in mRNA for GM-CSF, IL-1, IL-6, interferons, TNF, some growth factors, c-jun, c-fos, c-myc and c-myb. Upon the addi-... 

A. Kiimmel, S. Panke, and M. Heinemann, Putative regulatory sites unraveled by network embedded thermodynamic analysis of metabolome data. Mol. Syst. Biol. 2 (2006). 

In addition to the binding of substrate (or in some cases co-substrates) at the active site, many enzymes have the capacity to bind regulatory molecules at sites which are usually spatially far removed from the catalytic site. In fact, allosteric enzymes are invariably multimeric (i.e. have a quaternary structure) and the allosteric (regulatory) sites are on different subunits of the protein to the active site. In all cases, the binding of the regulatory molecules is non covalent and is described in kinetic terms as noncompetitive inhibition. 

The molecular mechanism underlying the inhibition remains unclear. It could comprise the simple product inhibition due to binding of PS to either catalytic site or the regulatory site of PSS I. It is also possible that a putative regulator molecule may bind PSS I to repress the PSS I activity in the presence of excess PS and that Arg-95 of PSS I may be essential for this binding. Determination of the three-dimensional structure of PSS I may provide a new insight into the role of Arg-95 of PSS I in the feedback regulation mechanism. 

Nowadays, it is a well-established fact that the effector R is not isosteric but allosteric to the substrate A. Originally, this conclusion was based on the finding that the enzyme can be desensitized, i.e., one can add substances that affect the regulatory site but not the activity of the enzyme with respect to the substrate. 

We extend the model of the previous section. Instead of one regulatory site we now have two sites, say R and / 2, which are identical and bind the effector R (Fig. 8.9). We still have one active site A, hence in the absence of the effector the binding isotherm 0 (Q, Cg = 0) is a simple Langmuir curve. 

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