A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

Vinitha N. Ragavan; Pramod C. Nair; Natalia Jarzebska; Ramcharan Singh Angom; Luana Ruta; Elisa Bianconi; Silvia Grottelli; Natalia D. Tararova; Daniel Ryazanskiy; Steven R. Lentz; Sara Tommasi; Jens Martens-Lobenhoffer; Toshiko Suzuki-Yamamoto; Masumi Kimoto; Elena Rubets; Sarah Chau; Yingjie Chen; Xinli Hu; Nadine Bernhardt; Peter M. Spieth; Norbert Weiss; Stefan R. Bornstein; Debabrata Mukhopadhyay; Stefanie M. Bode-Böger; Renke Maas; Ying Wang; Antonio Macchiarulo; Arduino A. Mangoni; Barbara Cellini; Roman N. Rodionov

doi:10.1038/s41467-023-38467-9

A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

Vinitha N. Ragavan, Pramod C. Nair, Natalia Jarzebska, Ramcharan Singh Angom, Luana Ruta, Elisa Bianconi, Silvia Grottelli, Natalia D. Tararova, Daniel Ryazanskiy, Steven R. Lentz, Sara Tommasi, Jens Martens-Lobenhoffer, Toshiko Suzuki-Yamamoto, Masumi Kimoto, Elena Rubets, Sarah Chau, Yingjie Chen, Xinli Hu, Nadine Bernhardt, Peter M. SpiethNorbert Weiss, Stefan R. Bornstein, Debabrata Mukhopadhyay, Stefanie M. Bode-Böger, Renke Maas, Ying Wang, Antonio Macchiarulo, Arduino A. Mangoni, Barbara Cellini, Roman N. Rodionov

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Abstract

Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

Original language	English
Article number	3392
Number of pages	16
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-38467-9
Publication status	Published - 9 Jun 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Enzyme mechanisms
Hydrolases
Metabolism
Molecular modelling

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Ragavan, V. N., Nair, P. C., Jarzebska, N., Angom, R. S., Ruta, L., Bianconi, E., Grottelli, S., Tararova, N. D., Ryazanskiy, D., Lentz, S. R., Tommasi, S., Martens-Lobenhoffer, J., Suzuki-Yamamoto, T., Kimoto, M., Rubets, E., Chau, S., Chen, Y., Hu, X., Bernhardt, N., ... Rodionov, R. N. (2023). A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase. Nature Communications, 14(1), Article 3392. https://doi.org/10.1038/s41467-023-38467-9

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title = "A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase",

abstract = "Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2{\textquoteright}s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.",

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author = "Ragavan, {Vinitha N.} and Nair, {Pramod C.} and Natalia Jarzebska and Angom, {Ramcharan Singh} and Luana Ruta and Elisa Bianconi and Silvia Grottelli and Tararova, {Natalia D.} and Daniel Ryazanskiy and Lentz, {Steven R.} and Sara Tommasi and Jens Martens-Lobenhoffer and Toshiko Suzuki-Yamamoto and Masumi Kimoto and Elena Rubets and Sarah Chau and Yingjie Chen and Xinli Hu and Nadine Bernhardt and Spieth, {Peter M.} and Norbert Weiss and Bornstein, {Stefan R.} and Debabrata Mukhopadhyay and Bode-B{\"o}ger, {Stefanie M.} and Renke Maas and Ying Wang and Antonio Macchiarulo and Mangoni, {Arduino A.} and Barbara Cellini and Rodionov, {Roman N.}",

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Ragavan, VN, Nair, PC, Jarzebska, N, Angom, RS, Ruta, L, Bianconi, E, Grottelli, S, Tararova, ND, Ryazanskiy, D, Lentz, SR, Tommasi, S, Martens-Lobenhoffer, J, Suzuki-Yamamoto, T, Kimoto, M, Rubets, E, Chau, S, Chen, Y, Hu, X, Bernhardt, N, Spieth, PM, Weiss, N, Bornstein, SR, Mukhopadhyay, D, Bode-Böger, SM, Maas, R, Wang, Y, Macchiarulo, A, Mangoni, AA, Cellini, B & Rodionov, RN 2023, 'A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase', Nature Communications, vol. 14, no. 1, 3392. https://doi.org/10.1038/s41467-023-38467-9

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AU - Ragavan, Vinitha N.

AU - Nair, Pramod C.

AU - Jarzebska, Natalia

AU - Angom, Ramcharan Singh

AU - Ruta, Luana

AU - Bianconi, Elisa

AU - Grottelli, Silvia

AU - Tararova, Natalia D.

AU - Ryazanskiy, Daniel

AU - Lentz, Steven R.

AU - Tommasi, Sara

AU - Martens-Lobenhoffer, Jens

AU - Suzuki-Yamamoto, Toshiko

AU - Kimoto, Masumi

AU - Rubets, Elena

AU - Chau, Sarah

AU - Chen, Yingjie

AU - Hu, Xinli

AU - Bernhardt, Nadine

AU - Spieth, Peter M.

AU - Weiss, Norbert

AU - Bornstein, Stefan R.

AU - Mukhopadhyay, Debabrata

AU - Bode-Böger, Stefanie M.

AU - Maas, Renke

AU - Wang, Ying

AU - Macchiarulo, Antonio

AU - Mangoni, Arduino A.

AU - Cellini, Barbara

AU - Rodionov, Roman N.

PY - 2023/6/9

Y1 - 2023/6/9

N2 - Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

AB - Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.

KW - Enzyme mechanisms

KW - Hydrolases

KW - Metabolism

KW - Molecular modelling

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A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

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