Serine racemase

Panizzutti, R., Miranda, J. de, Ribeiro, C. S., Engelender, S., Wolosker, H. A new strategy to decrease N-methyl-D-aspartate (NMDA) receptor coactivation inhibition of D-serine synthesis by converting serine racemase into an eliminase, Proc. Natl. Acad. Sci. USA 2001, 98, 5294-5299. 

Serine Racemase (EC 5.1.1.16] Serine racemases have been discovered in both bacteria and eukaryotes (for a review see [60, 62). In the latter organisms, serine racemase catalyzing the conversion of L-Ser to D-Ser was at first discovered in the silkworm Bombyx mori it is a PLP-dependent racemase which is also active on L-Ala (-6% of the activity on L-Ser). A serine racemase was also purified from rat brain (and a serine racemase cDNA was cloned from mouse brain). Mammalian serine racemase shows sequence simUarily with L-threonine dehydratase from various sources all the active site residues of the latter enzyme are also conserved in mouse serine racemase. Mammalian serine racemase is a member of the fold-type II group of PLP enzymes (similarly to L-threonine dehydratase, D-serine dehydratase, and so on) and distinct from alanine racemase, which belongs to the fold-type III group. Mouse serine racemase shows a low kinetic efficiency the Km values for L- and D-Ser are -10 and 60 mM, respectively and the V ax values with L- and D-Ser are 0.08 and 0.37 units/mg protein (less than 0.1% of those of alanine racemase on L- and D-Ala, see above). 

Amino acid racemases have long been known to be important in bacterial metabolism, because several u-amino acids are required for the synthesis of cell wall mucopolysaccharides. u-Serine is found in relatively large amounts in mammalian brain, where it acts as an agonist of the N-methyl-n-aspartate (NMDA) glutamate receptor. Serine racemase has been purified from rat brain and cloned fromhuman brain (Wolosker et al., 1999 De Miranda et al., 2000). 

De Miranda J, Santoro A, Engelender S, and Wolosker H (2000) Human serine racemase molecular cloning, genomic organization and functional analysis. Gene 256,183-8. 

Wolosker H, Sheth KN, Takahashi M, Mothet JP, Brady RO Jr, Ferris CD, and Snyder SH (1999) Purification of serine racemase biosynthesis of the neuromodulator D-serine. Proceedings of the Nationai Academy of Sciences of the USA96, 721-5. 

Serine racemase. The nervous system contains a substantial amount of d-serine, which is generated from 1-serine by serine racemase, a PLP-dependent enzyme. Propose a mechanism for this reaction. What is the equilibrium constant for the reaction 1-serine d-serine ... 

Snyder, S.H. Wolosker, H. Blackshaw, S. Serine racemase a glial enzyme synthesizing D-serine to regulate glutamate-V-methyl-D-aspartate neuro-transmission. Proc. Natl. Acad. Sci. USA 1999, 96, 13,409-13,414. 

Y354A mutant was shown to have significantly enhanced serine racemase activity... 

The presence of o-serine in mammalian brain tissue was first reported in 1989 [33, 34]. It has recently been established that o-serine is employed in the mammalian forebrain as a co-agonist for the N-methyl-o-asparate (NMDA) excitatory amino acid receptor [35, 36]. A PLP-dependent serine racemase has been cloned and purified from mammalian brain, and found to be a homodimer, which has a number of nonessential cofactors that enhance its activity, including Ca +, Mg + and ATP [37-40]. The mouse brain enzyme has also been shown to catalyze elimination from L-serine, to form pyruvate, with an activity comparable to that for racemiza-tion [41]. Interestingly, the first instance of this class of racemase was discovered by Esaki and coworkers in the silkworm, Bombyx mori [42]. o-serine concentration in the blood of B. mori larvae is thought to play a role in metamorphosis. 

Other amino acids such as L-aspartate and L-serine, can spontaneously racemize with aging in humans [149]. It has been reported that microwaving milk racemizes L-proline to D-proline, which could reduce the milk s nutritional value [150]. For L-serine, a serine racemase has been characterized that catalyzes the direct racemization of L-serine to D-serine. This enzyme can also catalyse D-serine to L-serine but with lesser affinity. As a number... 

Synthesis of phosphate precursors of natural products and other bioactive substances as well as total syntheses of biologically active phosphates including enantioselective approaches have been strongly represented in the literature this period, for instance the first synthesis of an unnatural phosphate analogue of plasmalogen, the synthesis of a mammalian serine racemase inhibitor, a highly convergent synthesis of fostriecin and the... 

Targeted MD ean be used when two states of a given protein are known, e.g., the open and elosed states of the binding pocket of serine racemase in a study of Bruno et al [59], An artificial force is applied during the MD to bias the transition between the two states. The need of a reaction coordinate limits this application to systems where a target stiucture is known beforehand. The trajectory of a targeted MD simulation can be used in the same way as ensembles derived fiom unbiased MD simulations [59]. 

Bruno A, Amori L, Costantino G (2011) Addressing the conformational flexibility of serine racemase by combining targeted molecular dynamics, conformational sampling and docking studies. Mol Inform 30(4) 317-328. doi 10.1002/minf.201000162... 

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