Biopterin metabolism and nitric oxide recoupling in cancer
Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in th...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-02-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1321326/full |
| _version_ | 1797295132976873472 |
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| author | Gene Chatman Clark Gene Chatman Clark Alan Lai Aashri Agarwal Zheng Liu Zheng Liu Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang |
| author_facet | Gene Chatman Clark Gene Chatman Clark Alan Lai Aashri Agarwal Zheng Liu Zheng Liu Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang |
| author_sort | Gene Chatman Clark |
| collection | DOAJ |
| description | Tetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns. |
| first_indexed | 2024-03-07T21:42:19Z |
| format | Article |
| id | doaj.art-36c3eb1b3b5548b485d0b4c9f5fcf7a2 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-07T21:42:19Z |
| publishDate | 2024-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-36c3eb1b3b5548b485d0b4c9f5fcf7a22024-02-26T04:50:27ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2024-02-011310.3389/fonc.2023.13213261321326Biopterin metabolism and nitric oxide recoupling in cancerGene Chatman Clark0Gene Chatman Clark1Alan Lai2Aashri Agarwal3Zheng Liu4Zheng Liu5Xiang-Yang Wang6Xiang-Yang Wang7Xiang-Yang Wang8Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, United StatesSchool of Medicine, Virginia Commonwealth University, Richmond, VA, United StatesSchool of Medicine, Virginia Commonwealth University, Richmond, VA, United StatesCornell University, Ithaca, NY, United StatesDepartment of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United StatesMassey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesDepartment of Human Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United StatesMassey Cancer Center, Virginia Commonwealth University, Richmond, VA, United StatesInstitute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, United StatesTetrahydrobiopterin is a cofactor necessary for the activity of several enzymes, the most studied of which is nitric oxide synthase. The role of this cofactor-enzyme relationship in vascular biology is well established. Recently, tetrahydrobiopterin metabolism has received increasing attention in the field of cancer immunology and immunotherapy due to its involvement in the cytotoxic T cell response. Past research has demonstrated that when the availability of BH4 is low, as it is in chronic inflammatory conditions and tumors, electron transfer in the active site of nitric oxide synthase becomes uncoupled from the oxidation of arginine. This results in the production of radical species that are capable of a direct attack on tetrahydrobiopterin, further depleting its local availability. This feedforward loop may act like a molecular switch, reinforcing low tetrahydrobiopterin levels leading to altered NO signaling, restrained immune effector activity, and perpetual vascular inflammation within the tumor microenvironment. In this review, we discuss the evidence for this underappreciated mechanism in different aspects of tumor progression and therapeutic responses. Furthermore, we discuss the preclinical evidence supporting a clinical role for tetrahydrobiopterin supplementation to enhance immunotherapy and radiotherapy for solid tumors and the potential safety concerns.https://www.frontiersin.org/articles/10.3389/fonc.2023.1321326/fulltetrahydrobiopterinradiotherapynitric oxide synthaseimmunotherapyimmunometabolismvascular normalization |
| spellingShingle | Gene Chatman Clark Gene Chatman Clark Alan Lai Aashri Agarwal Zheng Liu Zheng Liu Xiang-Yang Wang Xiang-Yang Wang Xiang-Yang Wang Biopterin metabolism and nitric oxide recoupling in cancer Frontiers in Oncology tetrahydrobiopterin radiotherapy nitric oxide synthase immunotherapy immunometabolism vascular normalization |
| title | Biopterin metabolism and nitric oxide recoupling in cancer |
| title_full | Biopterin metabolism and nitric oxide recoupling in cancer |
| title_fullStr | Biopterin metabolism and nitric oxide recoupling in cancer |
| title_full_unstemmed | Biopterin metabolism and nitric oxide recoupling in cancer |
| title_short | Biopterin metabolism and nitric oxide recoupling in cancer |
| title_sort | biopterin metabolism and nitric oxide recoupling in cancer |
| topic | tetrahydrobiopterin radiotherapy nitric oxide synthase immunotherapy immunometabolism vascular normalization |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1321326/full |
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