Modification of an Intervention to Improve Adherence in Adolescents and Young Adults With Bipolar Disorder.

Objective: Managing bipolar disorder (BD) is particularly challenging for adolescents and young adults (AYAs) ages 16 to 21. Few interventions exist that address self-management in AYAs with BD. Thus, this study aimed to modify the customized adherence enhancement behavioral intervention for AYAs through an iterative, patient-centered process.

A customized adherence enhancement program for adolescents and young adults with suboptimal adherence and bipolar disorder: Trial design and methodological report.

Background: The onset of bipolar disorder (BD) is common during late adolescence and young adulthood (AYA). Suboptimal medication adherence is a critical yet modifiable risk factor for negative outcomes among AYAs with BD.

Methods: This research used an iterative process (e.

Long-Acting Injectable Antipsychotic Medication Plus Customized Adherence Enhancement in Poor Adherence Patients With Bipolar Disorder.

People with bipolar disorder (BD) often have difficulty with medication adherence. This pilot trial combined a behavioral customized adherence enhancement (CAE) approach with long-acting injectable (LAI) antipsychotic medication and assessed effects on adherence, BD symptoms, and functional status. This 6-month prospective, uncontrolled trial of the intervention (CAE with LAI) in 30 poorly adherent individuals with BD assessed adherence using the Tablets Routine Questionnaire (TRQ) and symptoms using the Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HDRS), and Clinical Global Impressions (CGI).

Metabotype analysis of Mthfd1l-null mouse embryos using desorption electrospray ionization mass spectrometry imaging.

Mammalian folate-dependent one-carbon (1C) metabolism provides the building blocks essential during development via amino acid interconversion, methyl-donor production, regeneration of redox factors, and de novo purine and thymidylate synthesis. Folate supplementation prevents many neural tube defects (NTDs) that occur during the embryonic process of neurulation. The mechanism by which folate functions during neurulation is not well understood, and not all NTDs are preventable by folate supplementation.

Deletion of neural tube defect-associated gene Mthfd1l causes reduced cranial mesenchyme density.

Background: Periconceptional intake of supplemental folic acid can reduce the incidence of neural tube defects by as much as 70%, but the mechanisms by which folic acid supports cellular processes during neural tube closure are unknown. The mitochondrial 10-formyl-tetrahydrofolate synthetase MTHFD1L catalyzes production of formate, thus generating one-carbon units for cytoplasmic processes. Deletion of Mthfd1l causes embryonic lethality, developmental delay, and neural tube defects in mice.

Deletion of the neural tube defect-associated gene disrupts one-carbon and central energy metabolism in mouse embryos.

One-carbon (1C) metabolism is a universal folate-dependent pathway essential for purine and thymidylate synthesis, amino acid interconversion, universal methyl-donor production, and regeneration of redox cofactors. Homozygous deletion of the 1C pathway gene encoding methylenetetrahydrofolate dehydrogenase (NADP-dependent) 1-like, which catalyzes mitochondrial formate production from 10-formyltetrahydrofolate, results in 100% penetrant embryonic neural tube defects (NTDs), underscoring the central role of mitochondrially derived formate in embryonic development and providing a mechanistic link between folate and NTDs. However, the specific metabolic processes that are perturbed by deletion are not known.

Human mitochondrial MTHFD2 is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase.

Background: Folate-dependent one-carbon metabolism provides one-carbon units for several biological processes. This pathway is highly compartmentalized in eukaryotes, with the mitochondrial pathway producing formate for use in cytoplasmic processes. The mitochondrial enzyme MTHFD2 has been reported to use NAD as a cofactor while the isozyme MTHFD2L utilizes NAD or NADP at physiologically relevant conditions.

Mitochondrial one-carbon metabolism and neural tube defects.

Background: Neural tube defects (NTDs) are one of the most common birth defects in humans. Maternal intake of folic acid was linked to prevention of NTDs in the 1970s. This realization led to the establishment of mandatory and/or voluntary food folic acid fortification programs in many countries that have reduced the incidence of NTDs by up to 70% in humans.

Mitochondrial MTHFD2L is a dual redox cofactor-specific methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase expressed in both adult and embryonic tissues.

Mammalian mitochondria are able to produce formate from one-carbon donors such as serine, glycine, and sarcosine. This pathway relies on the mitochondrial pool of tetrahydrofolate (THF) and several folate-interconverting enzymes in the mitochondrial matrix. We recently identified MTHFD2L as the enzyme that catalyzes the oxidation of 5,10-methylenetetrahydrofolate (CH2-THF) in adult mammalian mitochondria.

Deletion of Mthfd1l causes embryonic lethality and neural tube and craniofacial defects in mice.

Maternal supplementation with folic acid is known to reduce the incidence of neural tube defects (NTDs) by as much as 70%. Despite the strong clinical link between folate and NTDs, the biochemical mechanisms through which folic acid acts during neural tube development remain undefined. The Mthfd1l gene encodes a mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase, termed MTHFD1L.

Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues.

Previous studies in our laboratory showed that isolated, intact adult rat liver mitochondria are able to oxidize the 3-carbon of serine and the N-methyl carbon of sarcosine to formate without the addition of any other cofactors or substrates. Conversion of these 1-carbon units to formate requires several folate-interconverting enzymes in mitochondria. The enzyme(s) responsible for conversion of 5,10-methylene-tetrahydrofolate (CH(2)-THF) to 10-formyl-THF in adult mammalian mitochondria are currently unknown.

Compartmentalization of Mammalian folate-mediated one-carbon metabolism.

The recognition that mitochondria participate in folate-mediated one-carbon metabolism grew out of pioneering work beginning in the 1950s from the laboratories of D.M. Greenberg, C.

Mitochondrial C1-tetrahydrofolate synthase (MTHFD1L) supports the flow of mitochondrial one-carbon units into the methyl cycle in embryos.

Mitochondrial folate-dependent one-carbon (1-C) metabolism converts 1-C donors such as serine and glycine to formate, which is exported and incorporated into the cytoplasmic tetrahydrofolate (THF) 1-C pool. Developing embryos depend on this mitochondrial pathway to provide 1-C units for cytoplasmic process such as de novo purine biosynthesis and the methyl cycle. This pathway is composed of sequential methylene-THF dehydrogenase, methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase activities.

Yeast AEP3p is an accessory factor in initiation of mitochondrial translation.

Initiation of protein synthesis in mitochondria and chloroplasts normally uses a formylated initiator methionyl-tRNA (fMet-tRNA(f)(Met)). However, mitochondrial protein synthesis in Saccharomyces cerevisiae can initiate with nonformylated Met-tRNA(f)(Met), as demonstrated in yeast mutants in which the nuclear gene encoding mitochondrial methionyl-tRNA formyltransferase (FMT1) has been deleted. The role of formylation of the initiator tRNA is not known, but in vitro formylation increases binding of Met-tRNA(f)(Met) to translation initiation factor 2 (IF2).

Human mitochondrial C1-tetrahydrofolate synthase: submitochondrial localization of the full-length enzyme and characterization of a short isoform.

Mammalian mitochondrial C(1)-tetrahydrofolate (THF) synthase (MTHFDIL gene product) is a monofunctional 10-formyl-THF synthetase, lacking the 5,10-methylene-THF dehydrogenase and 5,10-methenyl-THF cyclohydrolase activities typically found in the trifunctional cytoplasmic proteins. Here, we report the submitochondrial localization of epitope-tagged human mitochondrial C(1)-THF synthase expressed in Chinese hamster ovary cells. Mitochondrial fractionation experiments show that human mitochondrial C(1)-THF synthase behaves as a peripheral membrane protein, tightly associated with the matrix side of the mitochondrial inner membrane.

The gene for cobalamin-independent methionine synthase is essential in Candida albicans: a potential antifungal target.

Methionine synthase catalyzes the transfer of a methyl group from tetrahydrofolate to homocysteine to produce methionine. Although mammalian enzymes are cobalamin-dependent, fungal methionine synthases are cobalamin-independent. The opportunistic pathogen Candida albicans is a diploid and carries two copies of the methionine synthase gene, MET6.

Yeast mitochondrial initiator tRNA is methylated at guanosine 37 by the Trm5-encoded tRNA (guanine-N1-)-methyltransferase.

The TRM5 gene encodes a tRNA (guanine-N1-)-methyltransferase (Trm5p) that methylates guanosine at position 37 (m(1)G37) in cytoplasmic tRNAs in Saccharomyces cerevisiae. Here we show that Trm5p is also responsible for m(1)G37 methylation of mitochondrial tRNAs. The TRM5 open reading frame encodes 499 amino acids containing four potential initiator codons within the first 48 codons.

Global metabolic changes following loss of a feedback loop reveal dynamic steady states of the yeast metabolome.

Metabolic enzymes control cellular metabolite concentrations dynamically in response to changing environmental and intracellular conditions. Such real-time feedback regulation suggests the global metabolome may sample distinct dynamic steady states, forming "basins of stability" in the energy landscape of possible metabolite concentrations and enzymatic activities. Using metabolite, protein and transcriptional profiling, we characterize three dynamic steady states of the yeast metabolome that form by perturbing synthesis of the universal methyl donor S-adenosylmethionine (AdoMet).

Kinetic and structural analysis of active site mutants of monofunctional NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.

5,10-Methylenetetrahydrofolate dehydrogenase (MTD) catalyzes the reversible oxidation of 5,10-methylenetetrahydrofolate to 5,10-methenyltetrahydrofolate. This reaction is critical for the supply of one-carbon units at the required oxidation states for the synthesis of purines and dTMP. For most MTDs, dehydrogenase activity is co-located with a methenyl-THF cyclohydrolase activity as part of bifunctional or trifunctional enzyme.

Enzymatic characterization of human mitochondrial C1-tetrahydrofolate synthase.

A human mitochondrial isozyme of C1-tetrahydrofolate (THF) synthase was previously identified by its similarity to the human cytoplasmic C1-THF synthase. All C1-THF synthases characterized to date, from yeast to human, are trifunctional, containing the activities of 5,10-methylene-THF dehydrogenase, 5,10-methenyl-THF cyclohydrolase, and 10-formyl-THF synthetase. Here we report on the enzymatic characterization of the recombinant human mitochondrial isozyme.

Purification and properties of cobalamin-independent methionine synthase from Candida albicans and Saccharomyces cerevisiae.

In this study, we investigated methionine synthase from Candida albicans (CaMET 6p) and Saccharomyces cerevisiae (ScMET 6p). We describe the cloning of CaMet 6 and ScMet 6, and the expression of both the enzymes in S. cerevisiae.

Characterization of the C2 subdomain of yeast mitochondrial initiation factor 2.

The COOH-terminal part of the yeast mitochondrial initiation factor 2 (ymIF2), containing the C2 subdomain, was expressed and purified as a histidine-tagged polypeptide of 137 amino acids. Like the recombinant full-length protein, the C2 subdomain binds both formyl-Met-tRNA(f)(Met) and unformylated Met-tRNA(f)(Met) with only a small preference for the former species. Formation of a binary complex between the C2 subdomain or the full-length ymIF2 and initiator tRNA was also assessed by fluorescence measurements.

Characterization of the rat cytoplasmic C1-tetrahydrofolate synthase gene and analysis of its expression in liver regeneration and fetal development.

The eukaryotic trifunctional enzyme, C(1)-tetrahydrofolate (THF) synthase, interconverts folic acid derivatives between various oxidation states and is critical for normal cellular function, growth, and differentiation. Using a rat C(1)-THF synthase cDNA and synthetic oligonucleotides, the rat C(1)-THF synthase gene was isolated and characterized. The gene consists of 28 exons and spans 67.