Moiety conservation

One type of stoichiometric analysis concerns the discovery of moiety-conservation relationships in the network (Reder 1988 Famili and Palsson 2003 Nikolaev et al. 2005 Imielinski et al. 2006). These linear relationships represent sums of concentrations of intermediates in the network that remain constant on the time scale of interest, because there are only reactions that interconvert these particular intermediates. For instance, the following moiety-conservation relationship may pertain [Pi] + [AMP] + 2[ADP] -b 3[ATP]-b [other phosphate containing molecules] = [PJtotal constant. 

Sauro, H.M. (1994) Moiety-conserved cycles and metabolic control analysis problems in sequestration and metabolic channelling. Biosystems 55, 55-67. 

The classical MCA has been extended in a number of directions. For instance, Reder [1988] introduced a general methodology to calculate control coefficients from elasticities that takes into account moiety-conservation. Several papers have addressed enzyme-enzyme interactions in the context of MCA [e.g., Kacser, Sauro, and Acerenza 1990 Sauro and Kacser 1990]. 

The concentration of ATP in many types of healthy cells is 5 mM, while the concentration of ADP is much less at 0.2 mM AMP concentrations are typically 1 xM. The ratios of the concentrations of these adenine nucleotides are important in the control of metabolic processes. Except under extreme circumstances such as very fatigued muscle, the total concentration of the adenine nucleotide pool remains constant at 5 mM. The constancy of the total amount of recycled metabolites such as ATP is referred to as moiety conservation cells do this on time scales of hours to days. 

The electron carriers in the electron transport chain are limited in number. The concentration of ADP in the cell is low relative to ATP (Sec. 10.3), so once ADP is phosphorylated, no more ATP can be synthesized. Similarly, when NAD+ is reduced to NADH, it is no longer available for further oxidation of fuel molecules. The individual components of the electron transport chain must also continually pass on then-electrons to the next carrier otherwise, they remain fully reduced and are imable to accept electrons from the preceding electron carrier. Even compounds that participate in the metabolic pathways that generate NADH are in limited supply (recall moiety conservation in Sec. 10.3), and they too can become limiting unless they are regenerated. 

The palladium-catalyzed cyclization of compound 138 amply demonstrates the utility of the Stille reaction as a macrocyclization method (see Scheme 37). This efficient ring closure is just one of many examples disclosed by J.E. Baldwin and his group at Oxford.58 Interestingly, compound 138 can be employed as a stereoisomeric mixture of vinylstannanes because both stereoisomers converge on the same cyclized product. To rationalize this result, it was suggested that the configuration of the vinylstannane moiety is conserved in the cyclization, but that the macrocycle resulting from the (Z)-vinylstannane stereoisomer isomerizes to the thermodynamically favored trans product under the reaction condi-... 

With chiral auxiliaries1,41 a remote chiral moiety is temporarily introduced into the substrate in order to direct the nucleophilic addition diastereoselectively. The chiral auxiliary can be removed from the initial addition product with complete conservation of the chirality of the desired product and also of the chiral auxiliary. The recovered chiral auxiliary can then be reused in further reactions. Therefore, chiral auxiliaries are used to chiralize an a priori achiral carbonyl substrate by the introduction of a covalently bound, but nevertheless easily removable, chiral source. 

Many GPCRs contain one or more conserved cysteine residues within their C-terminal tails, which are modified by covalent attachment of palmitoyl or isoprenyl residues. The palmitoyl moiety is anchored in the lipid bilayer forming a fourth intracellular loop. There is evidence that palmitoylation of a GPCR is a dynamic process and may affect receptor desensitization. 

Phenylphosphate synthase consists of three subunits with molecular masses of 70, 40, and 24kDa. Subunit 1 resembles the central part of classical phospho-enolpyruvate synthase which contains a conserved histidine residue. It catalyzes the exchange of free [ C] phenol and the phenol moiety of phenylphosphate but not the phosphorylation of phenol. Phosphorylation of phenol requires subunit 1, MgATP, and another protein, subunit 2 (40kDa), which resembles the N-terminal part of phosphoenolpyruvate synthase. Subunit 1 and 2 catalyze the following reaction ... 

The abundance of structural information has led to a significant increase in the use of structure-based methods both to identify and to optimise inhibitors of protein kinases. The focus to date has centred upon small molecule ATP-competitive inhibitors and there are numerous examples of protein-ligand complexes available to guide design strategies. ATP binds in the cleft formed between the N- and C-terminal lobes of the protein kinase, forming several key interactions conserved across the protein kinase family. The adenine moiety lies in a hydrophobic region between the jS-sheet structure of subdomains I and II and residues from subdomains V and VIb. A... 

If a four-membered ring peroxide (1.2-dioxetane) is involved in a reaction, its concerted bond cleavage into two carbonyl moieties should yield one of these in its excited electronic state on the basis of the orbital symmetry conservation rules of R. B. Woodward and R. Hoffmann ... 

Material balances can be written for moieties which are conserved during the reaction, such as the atoms of a particular element or the total charge, or for reactant or product species if the stoichiometry is unambiguous. Oxidation-reduction reactions may be particularly troublesome. In the following situation, for example, one cannot write a material balance relating protons to water molecules. Consider the oxidation of O2 to H2O and the equilibrium dissociation of I O. 

In writing balance equations for the partial equilibrium model, two quantities are absolutely conserved. These are the total number of sulfate moieties and the net charge in solution. The resulting equations are ... 

The cytoplasmic NAD-reducing hydrogenase (SH) of the bacterium R. eutropha is a heterotetrameric enzyme, which contains several cofactors (Friedrich et al. 1996 Thiemermann et al. 1996). The Ni-containing subunit is called HoxH. This subunit plus the small subunit HoxY form the strictly conserved hydrogenase module with the Ni-Fe centre and a proximal [4Fe-4S] cluster. HoxF and HoxU represents the Fe-S/flavoprotein moiety which is closely related to a similar moiety in NADHrubiquinone oxidoreductase. The SH has been subject to molecular biological techniques in order to study its modular structure, mechanism and biosynthesis. 

---