Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.1.1.6 (CAD)
 4,420 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crystals of N-formyl-L-alanyl-L-aspartic acid (C8H11N2O6) grown from aqueous methanol solution are orthorhombic, space group, P2(1)2(1)2(1) with cell parameters at 294K of a = 13.619(2), b = 8.567(2), c = 9.583(3)A, V = 1118.1A3, M.W. = 232.2, Z = 4, Dm = 1.38 g/cm3 and Dx = 1.378 g/cm3. The crystal structure was solved by the application of direct methods and refined to an R value of 0.075 for 1244 reflections with I greater than or equal to 3 sigma collected on a CAD-4 diffractometer. The structure contains two short intermolecular hydrogen bonds: (i) between the C-terminal carboxyl OH and the N-acyl oxygen (2.624(3)A), a characteristic feature found in many N-acyl peptides and (ii) between the aspartic carboxyl OH. and the peptide oxygen OP1 (2.623(3)A). The peptide is nonplanar (omega = 165.5(6) degrees). The molecule takes up a folded conformation in contrast to N-formyl peptides which form extended beta-sheets; the values of phi 1, psi 1, phi 2, psi 2(1), and psi 2(2) are, respectively -65.7(6), 152.0(5), -107.2(5), 30.9(5), and -150.3(6). The aspartic acid side chain conformation is g- with chi 1 = 73.1(5). The formyl group, as expected, is transplanar [OF-CF-N1-CA1 = -4.0(8) degrees]. The presence of the short O-H ... O hydrogen bond emerges as a structural feature common to this peptide and several other N-formyl peptides. There are no C-H ... O hydrogen bonds in this structure.
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PMID:Conformation and hydrogen bonding of N-formylpeptides: crystal and molecular structure of N-formyl-L-alanyl-L-aspartic acid. 179 7

Deamidation of asparaginyl and isomerization of aspartyl residues in proteins proceed through a succinimide intermediate producing a mixture of aspartyl and isoaspartyl residues. Isoaspartic acid is an isomer of aspartic acid with the C(beta) incorporated into the backbone, thus increasing the length of the protein backbone by one methylene unit. This post-translation modification is suspected to contribute to the aging of proteins and to protein folding disorders such as Alzheimer's disease, so that differentiating the two isomers becomes important. This manuscript reports that distinguishing aspartyl from isoaspartyl residues in peptides has been accomplished by electron capture dissociation (ECD) using a Fourier transform mass spectrometer (FTMS). Model peptides with aspartyl residues and their isoaspartyl analogs were examined and unique peaks corresponding to c(n)*+58 and z(l-n)-57 fragment ions (n, position of Asp; l, total number of amino acids in the peptide) were found only in the spectra of the peptides with isoaspartyl residues. The proposed fragmentation mechanism involves cleavage of the C(alpha)-C(beta) backbone bond, therefore splitting the isoaspartyl residue between the two fragments. Also, a complementary feature observed specific to aspartyl residues was the neutral loss of the aspartic acid side chain from the charge reduced species. CAD spectra of the peptides from the same instrument demonstrated the improved method because previously published CAD methods rely on the comparison to the spectra of standards with aspartyl residues. The potential use of the top-down approach to detect and resolve products from the deamidation of asparaginyl and isomerization of aspartyl residues is discussed.
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PMID:Deamidation: Differentiation of aspartyl from isoaspartyl products in peptides by electron capture dissociation. 1565 75

In noradrenergic progenitors, Phox2a mediates cell cycle exit and neuronal differentiation by inducing p27(Kip1) transcription in response to activation of the cyclic AMP (cAMP) pathway. The mechanism of cAMP-mediated activation of Phox2a is unknown. We identified a cluster of phosphoserine-proline sites in Phox2a by mass spectrometry. Ser206 appeared to be the most prominent phosphorylation site. A phospho-Ser206 Phox2a antibody detected dephosphorylation of Phox2a that was dependent on activation of the cAMP pathway, which occurred prior to neuronal differentiation of noradrenergic CAD cells. Employing serine-to-alanine and serine-to-aspartic acid Phox2a substitution mutants expressed in inducible CAD cell lines, we demonstrated that the transcriptional activity of Phox2a is regulated by two sequential cAMP-dependent events: first, cAMP signaling promotes dephosphorylation of Phox2a in at least one site, Ser206, thereby allowing Phox2a to bind DNA and initiate p27(Kip1) transcription; second, following dephosphorylation of the phosphoserine cluster (Ser202 and Ser208), Phox2a becomes phosphorylated by protein kinase A (PKA) on Ser153, which prevents association of Phox2a with DNA and terminates p27(Kip1) transcription. This represents a novel mechanism by which the same stimulus, cAMP signaling, first activates Phox2a by dephosphorylation of Ser206 and then, after a built-in delay, inactivates Phox2a via PKA-dependent phosphorylation of Ser153, thereby modulating onset and duration of p27(Kip1) transcription.
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PMID:Time-dependent activation of Phox2a by the cyclic AMP pathway modulates onset and duration of p27Kip1 transcription. 1963 7