The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis
Folate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences t...
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MDPI AG
2020-05-01
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| Series: | Metabolites |
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| Online Access: | https://www.mdpi.com/2218-1989/10/5/184 |
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| author | Jan Geryk Daniel Krsička Markéta Vlčková Markéta Havlovicová Milan Macek Radka Kremlíková Pourová |
| author_facet | Jan Geryk Daniel Krsička Markéta Vlčková Markéta Havlovicová Milan Macek Radka Kremlíková Pourová |
| author_sort | Jan Geryk |
| collection | DOAJ |
| description | Folate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences to folate depletion in the metabolic network. Within the Flux Balance Analysis (FBA) framework, we developed a method of blocked metabolites that allowed us to define the metabolic consequences of various gene defects and folate depletion. We identified six genes (<i>GART</i>, <i>PFAS</i>, <i>PPAT</i>, <i>PAICS</i>, <i>ATIC</i>, and <i>ADSL</i>) whose blocking results in nearly the same effect in the metabolic network as folate depletion. All of these genes form the purine biosynthetic pathway. We found that, just like folate depletion, the blockade of any of the six genes mentioned above results in a blockage of purine metabolism. We hypothesize that this can lead to decreased adenosine triphosphate (ATP) and subsequently, an S-adenosyl methionine (SAM) pool in neurons in the case of rapid cell division. Based on our results, we consider the methylation defect to be a potential cause of ASD, due to the depletion of purine, and consequently S-adenosyl methionine (SAM), biosynthesis. |
| first_indexed | 2024-03-10T20:01:36Z |
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| id | doaj.art-94cd442271ed46bdb629f4f67b62e005 |
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| issn | 2218-1989 |
| language | English |
| last_indexed | 2024-03-10T20:01:36Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Metabolites |
| spelling | doaj.art-94cd442271ed46bdb629f4f67b62e0052023-11-19T23:33:39ZengMDPI AGMetabolites2218-19892020-05-0110518410.3390/metabo10050184The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico AnalysisJan Geryk0Daniel Krsička1Markéta Vlčková2Markéta Havlovicová3Milan Macek4Radka Kremlíková Pourová5Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech RepublicDepartment of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech RepublicDepartment of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech RepublicDepartment of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech RepublicDepartment of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech RepublicDepartment of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech RepublicFolate deficiency in the critical developmental period has been repeatedly associated with an increased risk of Autism spectrum disorders (ASD), but the key pathophysiological mechanism has not yet been identified. In this work, we focused on identifying genes whose defect has similar consequences to folate depletion in the metabolic network. Within the Flux Balance Analysis (FBA) framework, we developed a method of blocked metabolites that allowed us to define the metabolic consequences of various gene defects and folate depletion. We identified six genes (<i>GART</i>, <i>PFAS</i>, <i>PPAT</i>, <i>PAICS</i>, <i>ATIC</i>, and <i>ADSL</i>) whose blocking results in nearly the same effect in the metabolic network as folate depletion. All of these genes form the purine biosynthetic pathway. We found that, just like folate depletion, the blockade of any of the six genes mentioned above results in a blockage of purine metabolism. We hypothesize that this can lead to decreased adenosine triphosphate (ATP) and subsequently, an S-adenosyl methionine (SAM) pool in neurons in the case of rapid cell division. Based on our results, we consider the methylation defect to be a potential cause of ASD, due to the depletion of purine, and consequently S-adenosyl methionine (SAM), biosynthesis.https://www.mdpi.com/2218-1989/10/5/184autismASDfolateblocked metabolitepurine<i>ADSL</i> |
| spellingShingle | Jan Geryk Daniel Krsička Markéta Vlčková Markéta Havlovicová Milan Macek Radka Kremlíková Pourová The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis Metabolites autism ASD folate blocked metabolite purine <i>ADSL</i> |
| title | The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis |
| title_full | The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis |
| title_fullStr | The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis |
| title_full_unstemmed | The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis |
| title_short | The Key Role of Purine Metabolism in the Folate-Dependent Phenotype of Autism Spectrum Disorders: An In Silico Analysis |
| title_sort | key role of purine metabolism in the folate dependent phenotype of autism spectrum disorders an in silico analysis |
| topic | autism ASD folate blocked metabolite purine <i>ADSL</i> |
| url | https://www.mdpi.com/2218-1989/10/5/184 |
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