Syntheses of optically active 2-amino-4-oxobutyric acid and N,O-protected derivatives

Meffre, Patrick

doi:10.1007/bf01388171

Cited by 20 publications

(12 citation statements)

References 102 publications

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“…In solution, ASA is an unstable compound that polymerizes (16,50,64,79). We tested the hypothesis that ASA might cyclize to produce a compound analogous to L-azetidine-2-carboxylic acid, a toxic proline analogue.…”

Section: Discussionmentioning

confidence: 99%

FKBP12 Controls Aspartate Pathway Flux in Saccharomyces cerevisiae To Prevent Toxic Intermediate Accumulation

et al. 2004

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FKBP12 is a conserved member of the prolyl-isomerase enzyme family and serves as the intracellular receptor for FK506 that mediates immunosuppression in mammals and antimicrobial actions in fungi. To investigate the cellular functions of FKBP12 in Saccharomyces cerevisiae, we employed a high-throughput assay to identify mutations that are synthetically lethal with a mutation in the FPR1 gene, which encodes FKBP12. This screen identified a mutation in the HOM6 gene, which encodes homoserine dehydrogenase, the enzyme catalyzing the last step in conversion of aspartic acid into homoserine, the common precursor in threonine and methionine synthesis. Lethality of fpr1 hom6 double mutants was suppressed by null mutations in HOM3 or HOM2, encoding aspartokinase and aspartate ␤-semialdehyde dehydrogenase, respectively, supporting the hypothesis that fpr1 hom6 double mutants are inviable because of toxic accumulation of aspartate ␤-semialdehyde, the substrate of homoserine dehydrogenase. Our findings also indicate that mutation or inhibition of FKBP12 dysregulates the homoserine synthetic pathway by perturbing aspartokinase feedback inhibition by threonine. Because this pathway is conserved in fungi but not in mammals, our findings suggest a facile route to synergistic antifungal drug development via concomitant inhibition of FKBP12 and Hom6.Prolyl isomerases are widely conserved, ubiquitous enzymes that catalyze cis-trans isomerization of peptidyl-prolyl bonds, a reaction that can be rate limiting for protein folding. Founding members of this group of enzymes are cyclophilin A, previously identified as the cyclosporine A receptor (25,31,75), and the structurally unrelated enzyme FK506 binding protein FKBP12 (35). A third family of prolyl isomerases, known as the parvulins, was discovered for bacteria (60, 61) and later was found to be conserved in many other organisms.Cyclophilin A and FKBP12 mediate the immunosuppressive effects of cyclosporine A and FK506 in mammals by forming complexes with these drugs that bind to and inhibit the functions of calcineurin in T-cell activation (for a review, see reference 68). FKBP12 is also the receptor for the drug rapamycin, and the FKBP12-rapamycin complex inhibits the functions of the Tor proteins (36, 44). Both cyclophilin A and FKBP12 are conserved in budding yeast (where they are encoded by the CPR1 and FPR1 genes, respectively) and mediate calcineurin inhibition by cyclosporine A and FK506 (11,26,30,37,38,52,55,78,83) and Tor inhibition by rapamycin (36, 44). Saccharomyces cerevisiae expresses seven other cyclophilins (Cpr2 to Cpr8), three other FKBPs (Fpr2 to Fpr4), and a single parvulin (Ess1) (for a recent review, see reference 6).With the exception of Ess1, all yeast prolyl isomerases are dispensable for growth (18,32,34). However, cyclophilin A does become essential in cells compromised for Ess1 function, suggesting a functional overlap between these two structurally unrelated prolyl isomerases (4). Thus far, the endogenous functions that have been defined for these prot...

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Section: Discussionmentioning

confidence: 99%

FKBP12 Controls Aspartate Pathway Flux in Saccharomyces cerevisiae To Prevent Toxic Intermediate Accumulation

et al. 2004

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“…Research in our laboratories has recently focused on the synthesis of unusual amino acids (Reginato et al, 1997(Reginato et al, , 1998(Reginato et al, , 1999Meffre et al, 1999Meffre et al, , 2001Meffre, 1999;Dave et al, 2003) and in the course of our studies we reported the first synthesis of ethynyloxazolidine 1 (Fig. 1).…”

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confidence: 62%

Ethynylglycine Synthon from Garner′s Aldehyde: A Useful Precursor for the Synthesis of Non‐Natural Amino Acids

2006

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“…2 ASA manipulation has also proved to be important in the synthesis of pharmaceuticals, aroma and flavour chemicals, pesticides and herbicides, dyes and pigments. 5 ASA is difficult to synthesize and characterize since, like many amino aldehydes, it has a marked tendency to polymerize and is only stable in aqueous strong acid. [3][4][5] There are three methods for synthesizing (S)-ASA that are commonly used for biochemical studies.…”

Section: Introductionmentioning

confidence: 99%

“…5 ASA is difficult to synthesize and characterize since, like many amino aldehydes, it has a marked tendency to polymerize and is only stable in aqueous strong acid. [3][4][5] There are three methods for synthesizing (S)-ASA that are commonly used for biochemical studies. 3,6,7 The later methods 3,7 are derived from the original method of Black and Wright 6 which requires the ozonolysis of (S)-allylglycine.…”

Section: Introductionmentioning

confidence: 99%

Two complete syntheses of (S)-aspartate semi-aldehyde and demonstration that Δ2-tetrahydroisophthalic acid is a non-competitive inhibitor of dihydrodipicolinate synthase

Roberts¹,

Morris²,

Dobson³

et al. 2004

Arkivoc

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We report, in full, two 3-step syntheses of (S)-aspartate semi-aldehyde, an important synthetic and biosynthetic precursor, from diprotected aspartic acid. The first synthesis proceeds via a thioester, the second via a Weinreb amide. Each route yields pure (S)-aspartate semi-aldehyde in excellent yield. The utility of (S)-aspartate semi-aldehyde prepared in this manner was demonstrated with an inhibition study of dihydrodipicolinate synthase, wherein ∆ 2 -tetrahydroisophthalic acid is shown to be a non-competitive inhibitor with respect to both substrates.

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Syntheses of optically active 2-amino-4-oxobutyric acid and N,O-protected derivatives

Cited by 20 publications

References 102 publications

FKBP12 Controls Aspartate Pathway Flux in Saccharomyces cerevisiae To Prevent Toxic Intermediate Accumulation

FKBP12 Controls Aspartate Pathway Flux in Saccharomyces cerevisiae To Prevent Toxic Intermediate Accumulation

Ethynylglycine Synthon from Garner′s Aldehyde: A Useful Precursor for the Synthesis of Non‐Natural Amino Acids

Two complete syntheses of (S)-aspartate semi-aldehyde and demonstration that Δ2-tetrahydroisophthalic acid is a non-competitive inhibitor of dihydrodipicolinate synthase

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