Metabolism functional group addition

Phospholipase A2 enzymes also have other important metabolic functions in addition to the overall destruction of phospholipids as catalysed by digestive pancreatic or venom enzymes. An enzyme in mitochondrial membranes seems to be intimately connected with the energy state of this organelle. Thus, the phospholipase is inactive in fully coupled mitochondria and only becomes active when ATP and respiratory control drop to low levels. Also, the widespread distribution of phospholipases A2 allows many tissues to perform retailoring of the molecular species of membrane lipids by the Lands mechanism. In this process, named after Lands, the American biochemist who first described it, cleavage of the acyl group from the sn-2 position yields a lysophospholipid which can be re-acylated with a new fatty acid from acyl-CoA (Figure 7.8). 

Segall and coworkers described the in vitro mouse hepatic microsomal metabolism of the alkaloid senecionine (159) (Scheme 34). Several pyrrolizidine alkaloid metabolites were isolated from mouse liver microsomal incubation mixtures and identified (222, 223). Preparative-scale incubations with mouse liver microsomes enabled the isolation of metabolites for mass spectral and H-NMR analysis. Senecic acid (161) was identified by GC-MS comparison with authentic 161. A new metabolite, 19-hydroxysenecionine (160), gave a molecular ion consistent with the addition of one oxygen atom to the senecionine structure. The position to which the new oxygen atom had been added was made evident by the H-NMR spectrum. The three-proton doublet for the methyl group at position 19 of senecionine was absent in the NMR spectrum of the metabolite and was replaced by two signals (one proton each) at 3.99 and 3.61 ppm for a new carbinol methylene functional group. All other H-NMR spectral data were consistent for the structure of 160 as the new metabolite (222). 

Many drugs have functional groups that can be metabolized by the addition of water. The major functional groups involved are esters, amides, and epoxides. Several phase II metabolites such as sulfates and glucuronides, which will be discussed in Chapter 7, can also be hydrolyzed back to the parent drug. 

Pristine CNTs are hydrophobic and cause a lack of solubility in biological aqueous fluids such as blood. The poor solubility of CNTs in blood stream poses a major challenge to in vivo studies making behavior of CNTs difficult to predict and control (Kam et al., 2005 Zheng et al., 2003a, b). Therefore, modification of CNT surface to introduce hydrophilic, functional groups has been utilized in pharmaceutical applications (Lacerda et al., 2006). However, insufficient in vivo evaluation of both pristine and surface-modified CNTs has been performed to answer essential questions on CNT toxicology. Additional in vivo studies also required to devise the best method of administration, means of uptake, metabolism, and elimination of CNTs. The in vivo studies on CNTs performed to date are presented in Table 12.2. 

Recent developments have led to agents with a built-in functional group that allows more rapid metabolism. Initially, the presence of ester groupings, as in suxamethonium, allowed fairly rapid metabolism in the body via esterase enzymes that hydrolyse these linkages. The enzyme involved appears to be a non-specific serum acetylcholinesterase (see Box 13.4). Even better is the inclusion of functionalities that allow additional degradation via an elimination reaction. Such an agent is atracurium. 

Once inside the body, extremely hydrophilic compounds tend to be excreted more readily by the kidney. That could be useful, because it lowers toxicity. Additionally, chemical classes and functional groups known to be toxic—as well as those that can be bioactivated into toxic substances—should be avoided when designing chemical products. Chemicals can also be designed to shield active toxic sites or to facilitate metabolic degradation to nontoxic metabolites. 

Vitamins, cofactors, and metals have the potential to broaden the scope of antibody catalysis considerably. In addition to hydrolytic and redox reactions, they facilitate many complex functional group interconversions in natural enzymes.131 Pyridoxal, for example, plays a central role in amino acid metabolism. Among the reactions it makes possible are transaminations, decarboxylations, racemizations, and (3,y-eliminations. It is also essential for ethylene biosynthesis. Not surprisingly, then, several groups have sought to incorporate pyridoxal derivatives into antibody combining sites. 

The network operates through a series of enzyme-catalyzed reactions that constitute the metabolism. Each of the consecutive steps in a metabolic pathway brings about a specific chemical change, usually the removal, transfer, or addition of a particular atom or functional group. The precursor is converted into a product through a series of metabolic intermediates called metabolites. The term intermediary metabolism is often applied to the combined activities of all the metabolic pathways that interconvert precursors, metabolites, and products of low molecular weight. 

Thiamin was the first of the vitamins to be demonstrated to have a clearly defined metabolic function as a coenzyme indeed, the studies of Peters group in the 1920s and 1930s laid the foundations not only of nutritional biochemistry but also of modern metabolic biochemistry and neurochemistry. Despite this, the mechanism by which thiamin deficiency results in central and peripheral nervous system lesions remains unclear in addition to its established coenzyme role, thiamin regulates the activity of a chloride transporter in nerve cells. 

There are, in addition to these simple functional group filters, a number of property-based filters that may be applied. These fdters take the form of calculated metrics, such as the Lipinski Rule of Five (LRoF Hydrogen-bond donors. Hydrogen-bond acceptors, Lipophilicity, Molecular weight). Solubility, total Polar Surface Area (tPS A), Blood-brain-barrier (BBB) Permeability, calculated metabolic filters (cADMET Absorption-Distribution-Metabolism-Excretion-Toxicity) and Bioavailability. 

Figure 14.17. Metabolic Motifs. Some metabolic path vays have similar sequences of reactions in common in this case, an oxidation, the addition of a functional group (from a vv ater molecule) to a double bond, and another oxidation. ACP designates acyl carrier protein.

The series of products created by the sequential enzymatic steps of anabolism or catabolism are called metabolic intermediates, or metabolites. Each step represents a small change in the molecule, usually the removal, transfer, or addition of a specific atom, molecule or group of atoms that serves as a functional group, such as the amino groups (-NH2) of proteins. 

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