Biochemical signaling modules

The central dogma of molecular biology describes how one form of biological information (an organism s genetic sequence) is processed in terms of DNA replication, RNA transcription, and protein synthesis. However, a related mystery is yet to be worked out in sufficient detail how is the information encoded in the DNA (i.e., genotypes) related to cellular functions (i.e., phenotypes) How do different signals tell different cells to synthesize different proteins  

A central question in cellular biology is now to elucidate (meaning to develop models with reliable predictive power) the mechanisms by which the cells transduce information and perform their functions. Cellular biochemical signaling systems are customarily visualized as logic circuits the components for the circuitry, now popularly called modules [78], consist of molecules and biochemical reactions. Hence they can be subjected to kinetic and thermodynamic analysis as we have introduced in the previous chapters. In this chapter, we study several such modules that occur widely in cellular biology. 

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Most of the antibiotics commercially available nowadays are derivatives of natural compounds produced by bacteria or fungi. It is widely accepted that in nature these secondary metabolites can act as weapons for microbial cell defence, inhibiting the growth of competitors. However, it seems that antibiotics have, in nature, more sophisticated and complex functions [1-3]. Many environmental bacteria can not only cope with natural antimicrobial substances but also benefit from their presence. For instance, the use of antibiotics by bacteria as biochemical signals, modulators of metabolic activity or even carbon sources has been demonstrated [1, 2, 4]. In other cases, antibiotics can be tolerated because they have structures similar to the natural substrates of bacterial housekeeping enzymes and thus are inactivated, leading to a natural form of resistance [2]. These are just some... 

Whitmarsh, A.J. and Davis, R.J. Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals (1998) Trends Biochem Sci 23, 481-485... 

If we concentrate on one particular component of this map - the phosphorylation of PI(4,5)P2 to PI(3,4,5)P3 by PI3K and the dephosphorylation of PI(3,4,5)P3 to PI(4,5)P2 by F TEN, we can study the detailed enzyme kinetic scheme of this so-called phosphorylation-dephosphorylation cycle, which is illustrated in Figure 5.2. This illustrated cycle represents a ubiquitous module in biochemical signaling, ft could, for example, represent the phosphorylation of mitogen-activation protein kinase (MAPK) by MAPK kinase (MAPKK) and dephosphorylation of MAPK by MAPK phosphatase (MKP). 

In analyzing the temporal behavior of a biochemical switching molecule, we can study either of the equivalent models of the phosphorylation-dephosphorylation cycle or the GTPase signaling module. In particular, we are interested in the duration of each activation event at the single-molecule level. 

In animal models, nerve injury to the dorsal root results in the development of behavioral allodynia and hyperalgesia paralleled by demyelination. Intrathecal injection of LPA, but not SIP, initiates behavioral, morphological, and biochemical symptoms of neuropathic pain via an LPAi-mediated Rho/Rho-kinase pathway (Inoue et al., 2004). LPA signaling modulation may be relevant for some forms of neuropathic pain, an area of significant, unmet medical need (Dworkin et al., 2007). 

Bohm SK, Grady EF, Bunnett NW (1997) Regulatory mechanisms that modulate signalling by G-protein-coupled receptors. Biochem J 322 1-18... 

Palozza, R, Serini, S., Di Nicuolo, R, and Calviello, G. 2004b. Modulation of apoptotic signalling by carotenoids in cancer cells. Arch Biochem Biophys 430 104-109. 

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