Serine, brain

Mirror-image serine. Brain tissue contains substantial amounts of d-serine which is generated from 1-serine by serine racemase, a PLP enzyme. Propose a mechanism for the interconversion of 1- and d-serine. What is the equilibrium constant for the reaction 1-serine d-serine ... 

The inhibition of brain cholinesterase is a biomarker assay for organophosphorous (OP) and carbamate insecticides (Chapter 10, Section 10.2.4). OPs inhibit the enzyme by forming covalent bonds with a serine residue at the active center. Inhibition is, at best, slowly reversible. The degree of toxic effect depends upon the extent of cholinesterase inhibition caused by one or more OP and/or carbamate insecticides. In the case of OPs administered to vertebrates, a typical scenario is as follows sublethal symptoms begin to appear at 40-50% inhibition of cholinesterase, lethal toxicity above 70% inhibition. 

These compounds constimte as much as 10% of the phospholipids of brain and muscle. StmcmraUy, the plasmalogens resemble phosphatidylethanolamine but possess an ether link on the sn- carbon instead of the ester link found in acylglycerols. Typically, the alkyl radical is an unsamrated alcohol (Figure 14-10). In some instances, choline, serine, or inositol may be sub-stimted for ethanolamine. 

A competitive version of ABPP identifies the target(s) and assesses the selectivity of an enzyme inhibitor in biological systems by gauging how well the inhibitor slows the enzyme s reaction with an ABP. For example, fluorophosphonate ABP 3 was used to profile the selectivity of fatty acid amide hydrolase (FAAH) inhibitors within the serine hydrolase superfamily [27] (FAAH hydrolyzes endocannabinoids such as anandamide). Serine hydrolases that exhibited reduced labeling by the probe in the presence of inhibitor were scored as targets of the inhibitor. Urea FAAH inhibitors exemplified by PF-3845 (5) that covalently modify the active-site serine nucleophile of FAAH were found to be exquisitely selective for FAAH in brain and liver... 

The brain contains multiple forms of protein serine-threonine phosphatases 399... 

Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation. These properties determine the functional roles played by the very large number of protein kinases that have been found in mammalian tissues, most of which are known to be expressed in neurons [3]. The major classes of protein serine-threonine kinase in the brain, listed in Table 23-1, are covered in this chapter. The major classes of protein tyrosine kinases in the brain are discussed in Chapter 24. 

Price, N. E. and Mumby, M. C. Brain protein serine/ threonine phosphatases. Curr. Opin. Neurobiol. 9 336-342, 1999. 

Filamentous tau is hyperphosphorylated. This is an early event that appears to precede filament assembly. It also renders tau unable to interact with microtubules. Much effort has gone into the mapping of phosphorylation sites and the identification of candidate protein kinases and phosphatases. For sites that are also phos-phorylated in normal brain tau, a higher proportion of tau molecules is phosphorylated in filamentous tau. In addition, filamentous tau is phosphorylated at more serine and threonine residues than tau from normal adult brain. Phosphorylation-dependent anti-tau antibodies were instrumental for the study of many phosphorylation sites. In particular, phosphorylation of S214 and S422 was found to be specific for assembled tau. 

Calcineurin is a serine/threonine protein phosphatase widely distributed in the brain, but its role in brain function remains unknown. It is critical for several important cellular processes including T-cell activation, and recent data indicate that it may be involved in hyperphosphorylation of tau in Alzheimer s disease (600, 601). The active site of native calcineurin contains zinc and iron metal ions and three metal-bound water molecules (602), one of which may be involved in nucleophilic attack on the substrate. Compound 119 (FK506, tacroli-... 

Phosphatidyl serines (or threonine) nh3 —ch2ch.cooh Widely distributed but in small amounts. Is a major component of brain and red cell lipids Usually isolated as salts with K+, Ca2+, Na+ or Mg2+... 

Glycogen phosphorylase isoenzymes have been isolated from liver, brain and skeletal muscle. All forms are subject to covalent control with conversion of the inactive forms (GP-b) to the active forms (GP-a) by phosphorylation on specific serine residues. This phosphorylation step, mediated by the enzyme phosphorylase kinase, is initiated by glucagon stimulation of the hepatocyte. Indeed, the same cAMP cascade which inhibits glycogen synthesis simultaneously stimulates glycogenolysis, giving us an excellent example of reciprocal control. 

Hashimoto A, Nishikawa T, Hayashi T, Fujii N, Harada K, et al. 1992. The presence of free D-serine in rat brain. Federat Europ Biochem Soc 296 33. 

Abood and coworkers (IJ-IS) have reported that acidic lipids, in particular phosphatidyl serine (PS), enhanced binding of opiates to membranous components of brain. Furthermore, PS has been shown to bind opiates stereospecifically whereas other acidic lipids bind to a lesser extent and neutral lipids bind very little (1 1). Loh and coworkers (14-16,) have reported that cerebroside Issued as N.R.C.C. Publication No. 17068. 

The anandamide precursor, phosphatidylethanol amine, is present in membranes almost always accompanied by phophatidylserine. It seemed reasonable to expect the formation of anandamide from its precursor will be paralleled by formation of N-arachidinoylserine from phosphatidyl serine. Indeed, A -arachidonoyl-L-serine (ARA-S) was found to be formed alongside anandamide (Fig. 4). This compound was isolated from bovine brain and its structure was elucidated by comparison with synthetic ARA-S. Contrary to anandamide, ARA-S binds very weakly to the known cannabinoid CBi and CB2 or vanilloid TRPVl receptors. However, it produces endothelium-dependent vasodilation of rat isolated mesenteric... 

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