Some properties and a suggested reclassification of mevaldate reductase.
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ABSTRACT:
SUBMITTER: Beedle AS
PROVIDER: S-EPMC1166268 | biostudies-other | 1974 Apr
REPOSITORIES: biostudies-other
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Project description:PurposeThe Index of Productive Syntax (IPSyn) is a well-known language sample analysis tool. However, its psychometric properties have not been assessed across a wide sample of typically developing preschool-age children and children with language disorders. We sought to determine the profile of IPSyn scores by age over early childhood. We additionally explored whether the IPSyn could be shortened to fewer items without loss of information and whether the required language sample could be shortened from a current required number of 100 utterances to 50.MethodWe used transcripts from the Child Language Data Exchange System, including 1,051 samples of adult-child conversational play with toys within the theoretical framework of item response theory. Samples included those from typically developing children as well as children with hearing loss, Down syndrome, and late language emergence.ResultsThe Verb Phrase and Sentence Structure subscales showed more stable developmental trajectories over the preschool years and greater differentiation between typical and atypical cohorts than did the Noun Phrase and Question/Negation subscales. A number of current IPSyn scoring items can be dropped without loss of information, and 50-utterance samples demonstrate most of the same psychometric properties of longer samples.DiscussionOur findings suggest ways in which the IPSyn can be automated and streamlined (proposed IPSyn-C) so as to provide useful clinical guidance with fewer items and a shorter required language sample. Reference values for the IPSyn-C are provided. Trajectories for one subscale (Question/Negation) appear inherently unstable and may require structured elicitation. Potential limitations, ramifications, and future directions are discussed.Supplemental materialhttps://doi.org/10.23641/asha.16915690.
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Project description:BackgroundMethylenetetrahydrofolate reductase (MTHFR) is one of the enzymes involved in homocysteine metabolism. Despite considerable genetic and clinical attention, the reaction mechanism and regulation of this enzyme are not fully understood because of difficult production and poor stability. While recombinant enzymes from thermophilic organisms are often stable and easy to prepare, properties of thermostable MTHFRs have not yet been reported.Methodology/principal findingsMTHFR from Thermus thermophilus HB8, a homologue of Escherichia coli MetF, has been expressed in E. coli and purified. The purified MTHFR was chiefly obtained as a heterodimer of apo- and holo-subunits, that is, one flavin adenine dinucleotide (FAD) prosthetic group bound per dimer. The crystal structure of the holo-subunit was quite similar to the β(8)α(8) barrel of E. coli MTHFR, while that of the apo-subunit was a previously unobserved closed form. In addition, the intersubunit interface of the dimer in the crystals was different from any of the subunit interfaces of the tetramer of E. coli MTHFR. Free FAD could be incorporated into the apo-subunit of the purified Thermus enzyme after purification, forming a homodimer of holo-subunits. Comparison of the crystal structures of the heterodimer and the homodimer revealed different intersubunit interfaces, indicating a large conformational change upon FAD binding. Most of the biochemical properties of the heterodimer and the homodimer were the same, except that the homodimer showed ≈50% activity per FAD-bound subunit in folate-dependent reactions.Conclusions/significanceThe different intersubunit interfaces and rearrangement of subunits of Thermus MTHFR may be related to human enzyme properties, such as the allosteric regulation by S-adenosylmethionine and the enhanced instability of the Ala222Val mutant upon loss of FAD. Whereas E. coli MTHFR was the only structural model for human MTHFR to date, our findings suggest that Thermus MTHFR will be another useful model for this important enzyme.
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Project description:Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of methylenetetrahydrofolate to methyltetrahydrofolate, the major methyl donor for the conversion of homocysteine to methionine. Two common polymorphisms of the human enzyme have been identified: 677C>T, which leads to the substitution of Ala-222 by valine, and 1298A>C, which leads to the replacement of Glu-429 by alanine; the former polymorphism is the most frequent genetic cause of mild hyperhomocysteinemia, a risk factor for cardiovascular disease. By using a baculovirus expression system, recombinant human MTHFR has been expressed at high levels and purified to homogeneity in quantities suitable for biochemical characterization. The Glu429Ala protein has biochemical properties that are indistinguishable from the wild-type enzyme. The Ala222Val MTHFR, however, has an enhanced propensity to dissociate into monomers and to lose its FAD cofactor on dilution; the resulting loss of activity is slowed in the presence of methyltetrahydrofolate or adenosylmethionine. This biochemical phenotype is in good agreement with predictions made on the basis of studies comparing wild-type Escherichia coli MTHFR with a mutant, Ala177Val, homologous to the Ala222Val mutant human enzyme [Guenther, B. D., et al. (1999) Nat. Struct. Biol. 6, 359-365].
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