The Molecular Evolution of Pyridoxal‐5′‐Phosphate‐Dependent Enzymes

Mehta, Perdeep K.; Christen, Philipp

doi:10.1002/9780470123201.ch4

Cited by 140 publications

(165 citation statements)

References 150 publications

(106 reference statements)

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“…1) (i.e. with maximum distance between the phosphate and the ␣-carboxylate group) is also observed in mAspAT and DaAT; it corresponds to the minimum energy conformation of the adduct and is assumed to result in stronger binding to the protein (28,29).…”

Section: Resultsmentioning

confidence: 99%

“…In all aminotransferases, the active-site lysine residue that covalently binds the cofactor is also responsible for the proton abstraction from C␣ of the amino acid and the reprotonation at C4Ј of PLP in the tautomerization of aldimine 4 to ketimine intermediate 5 (29,30). Substitution of Schiff base-forming Lys-258 in mAspAT with alanine, arginine, or cysteine leads to inactivation.…”

Section: Resultsmentioning

confidence: 99%

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Structural Basis for D-Amino Acid Transamination by the Pyridoxal 5′-Phosphate-dependent Catalytic Antibody 15A9

Golinelli‐Pimpaneau

Lüthi

Christen

2006

Journal of Biological Chemistry

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Antibody 15A9, raised with 5-phosphopyridoxyl (PPL)-N⑀ -acetyl-L-lysine as hapten, catalyzes the reversible transamination of hydrophobic D-amino acids with pyridoxal 5-phosphate (PLP). The crystal structures of the complexes of Fab 15A9 with PPL-L-alanine, PPL-D-alanine, and the hapten were determined at 2.3, 2.3, and 2.5 Å resolution, respectively, and served for modeling the complexes with the corresponding planar imine adducts. The conformation of the PLP-amino acid adduct and its interactions with 15A9 are similar to those occurring in PLPdependent enzymes, except that the amino acid substrate is only weakly bound, and, due to the immunization and selection strategy, the lysine residue that covalently binds PLP in these enzymes is missing. However, the N-acetyl-L-lysine moiety of the hapten appears to have selected for aromatic residues in hypervariable loop H3 (Trp-H100e and Tyr-H100b), which, together with Lys-H96, create an anion-binding environment in the active site. The structural situation and mutagenesis experiments indicate that two catalytic residues facilitate the transamination reaction of the PLP-D-alanine aldimine. The space vacated by the absent L-lysine side chain of the hapten can be filled, in both PLP-alanine aldimine complexes, by mobile Tyr-H100b. This group can stabilize a hydroxide ion, which, however, abstracts the C␣ proton only from D-alanine. Together with the absence of any residue capable of deprotonating C␣ of L-alanine, Tyr-H100b thus underlies the enantiomeric selectivity of 15A9. The reprotonation of C4 of PLP, the rate-limiting step of 15A9-catalyzed transamination, is most likely performed by a water molecule that, assisted by Lys-H96, produces a hydroxide ion stabilized by the anion-binding environment.The most often used approach for generating catalytic antibodies is to elicit antibodies against a haptenic group that mimics the transition state of the target reaction (1). The crystal structures of several antibodies obtained in this way validate this procedure and show the catalytic antibodies to bind and stabilize the transition state through van der Waals, hydrogen bonding, and electrostatic interactions (2, 3). Only by chance, these antibodies possess residues at the combining site that directly participate in the covalence changes of the reaction. The lack of catalytic residues is one of the reasons why the rate enhancement brought about by catalytic antibodies only occasionally approaches that of enzymes. The "bait and switch" strategy, which uses a charged hapten to elicit a programmed chemically reactive charged residue (4, 5), and the related procedure of "reactive immunization" (6) have been developed for obtaining catalytic antibodies endowed with reactive residues. Another possibility is to expand the catalytic scope of antibodies by incorporating a nonproteinaceous cofactor (7) that contributes to the catalytic efficacy while the antibody ensures substrate specificity and possibly reaction specificity. As yet, the structure of only one catalytic antibody tha...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Structural Basis for D-Amino Acid Transamination by the Pyridoxal 5′-Phosphate-dependent Catalytic Antibody 15A9

Golinelli‐Pimpaneau

Lüthi

Christen

2006

Journal of Biological Chemistry

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“…AGXT2L1 was the most consistently upregulated gene in the brains of deceased patients with schizophrenia or bipolar disorder (Shao and Vawter 2008) and was the most upregulated gene in mouse brain after treatment with lithium (McQuillin et al 2007). This is an example of an enzyme from a generalist family [class II aminotransferases (Mehta and Christen 2000)] which has become highly specific. Nam et al (2012) noted that specialist enzymes are frequently essential, maintain higher metabolic flux, and require more regulation to control metabolic flux in dynamic environments.…”

Section: Phosphoethanolamine Metabolismmentioning

confidence: 99%

Vitamin B-6 Metabolism and Interactions with TNAP

Coburn

2015

Subcellular Biochemistry

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“…One of the biologically active forms of vitamin B 6 is pyridoxal 5 0 -phosphate (PLP), which is essential for many enzyme reactions such as transamination, decarboxylation, racemization and elimination in amino-acid metabolism, DNA biosynthesis and biosynthesis of antibiotic compounds (Eliot & Kirsch, 2004;Mehta & Christen, 2000;Percudani & Peracchi, 2003). There are two pathways for de novo PLP biosynthesis and both pathways exist in bacteria, fungi, protozoa and plants, whereas they are missing in mammals (Belitsky, 2004;Dong et al, 2004;Osmani et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Overexpression, crystallization and preliminary X-ray crystallographic analysis of pyridoxal biosynthesis lyase PdxS fromPyrococcus horikoshii

et al. 2012

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Pyridoxal biosynthesis lyase (PdxS) is an important player in the biosynthesis of pyridoxal 5 0 -phosphate (PLP), the biologically active form of vitamin B 6 . PLP is an important cofactor involved in the metabolic pathway of amine-containing natural products such as amino acids and amino sugars. PdxS catalyzes the condensation of ribulose 5-phosphate (Ru5P), glyceraldehyde 3-phosphate (G3P) and ammonia, while glutamine amidotransferase (PdxT) catalyzes the production of ammonia from glutamine. PdxS and PdxT form a complex, PLP synthase, and widely exist in eubacteria, archaea, fungi and plants. To facilitate further structural comparisons among PdxS proteins, the structural analysis of PdxS from Pyrococcus horikoshii encoded by the Ph1355 gene was initiated. PdxS from P. horikoshii was overexpressed in Escherichia coli and crystallized at 296 K using 2-methyl-2,4-pentanediol as a precipitant. Crystals of P. horikoshii PdxS diffracted to 2.61 Å resolution and belonged to the monoclinic space group P2 1 , with unit-cell parameters a = 59.30, b = 178.56, c = 109.23 Å , = 102.97 . The asymmetric unit contained six monomers, with a corresponding V M of 2.54 Å 3 Da À1 and a solvent content of 51.5% by volume.

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The Molecular Evolution of Pyridoxal‐5′‐Phosphate‐Dependent Enzymes

Cited by 140 publications

References 150 publications

Structural Basis for D-Amino Acid Transamination by the Pyridoxal 5′-Phosphate-dependent Catalytic Antibody 15A9

Structural Basis for D-Amino Acid Transamination by the Pyridoxal 5′-Phosphate-dependent Catalytic Antibody 15A9

Vitamin B-6 Metabolism and Interactions with TNAP

Overexpression, crystallization and preliminary X-ray crystallographic analysis of pyridoxal biosynthesis lyase PdxS fromPyrococcus horikoshii

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