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Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods.

ABSTRACT: The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study's objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes, we investigated co-expression patterns with DDAH1 and DDAH2 in the dorsolateral prefrontal cortex in psychiatric patients and control subjects. There were no significant differences in DDAH1 and DDAH2 expression levels in schizophrenia or bipolar disorder patients compared to controls. Meanwhile, the data suggest that in patients, DDAH1 and DDHA2 undergo a functional shift mirrored in changes in co-expressed gene patterns. This disarrangement appears in the loss of expression level correlations between DDAH1 or DDAH2 and genes associated with psychiatric disorders and reduced functional similarity of DDAH1 or DDAH2 co-expressed genes in the patient groups. Our findings evidence the possible involvement of DDAH1 and DDAH2 in neuropsychiatric disorder development, but the underlying mechanisms need experimental validation.

SUBMITTER: Kozlova AA

PROVIDER: S-EPMC9569903 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods.

Kozlova Alena A AA Vaganova Anastasia N AN Rodionov Roman N RN Gainetdinov Raul R RR Bernhardt Nadine N

International journal of molecular sciences 20221007 19

The contribution of nitric oxide synthases (NOSs) to the pathophysiology of several neuropsychiatric disorders is recognized, but the role of their regulators, dimethylarginine dimethylaminohydrolases (DDAHs), is less understood. This study's objective was to estimate DDAH1 and DDAH2 associations with biological processes implicated in major psychiatric disorders using publicly accessible expression databases. Since co-expressed genes are more likely to be involved in the same biologic processes ...[more]

PMID: 36233204

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Project description:The tryptophan hydroxylase 2 (TPH2) enzyme catalyzes the first step of serotonin biosynthesis. Serotonin is known for its role in several homeostatic systems related to sleep, mood, and food intake. As the reaction catalyzed by TPH2 is the rate-limiting step of serotonin biosynthesis, mutations in TPH2 have been associated with several psychiatric disorders (PD). This work undertakes an in silico analysis of the effects of genetic mutations in the human TPH2 protein. Ten algorithms were used to predict the functional and stability effects of the TPH2 mutations. ConSurf was used to estimate the evolutionary conservation of TPH2 amino acids. GROMACS was used to perform molecular dynamics (MD) simulations of TPH2 WT and P260S, R303W, and R441H, which had already been associated with the development of PD. Forty-six TPH2 variants were compiled from the literature. Among the analyzed variants, those occurring at the catalytic domain were shown to be more damaging to protein structure and function. The ConSurf analysis indicated that the mutations affecting the catalytic domain were also more conserved throughout evolution. The variants S364K and S383F were predicted to be deleterious by all the functional algorithms used and occurred at conserved positions, suggesting that they might be deleterious. The MD analyses indicate that the mutations P206S, R303W, and R441H affect TPH2 flexibility and essential mobility at the catalytic and oligomerization domains. The variants P206S, R303W, and R441H also exhibited alterations in dimer binding affinity and stability throughout the simulations. Thus, these mutations may impair TPH2 functional interactions and, consequently, its function, leading to the development of PD. Furthermore, we developed a database, SNPMOL (http://www.snpmol.org/), containing the results presented in this paper. Understanding the effects of TPH2 mutations on protein structure and function may lead to improvements in existing treatments for PD and facilitate the design of further experiments.

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Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods.

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Assessment of DDAH1 and DDAH2 Contributions to Psychiatric Disorders via In Silico Methods.

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