2JAI

DDAH1 complexed with citrulline

2JAI の概要

• エントリーDOI: 10.2210/pdb2jai/pdb
• 関連するPDBエントリー: 1H70 2JAJ
• 分子名称: NG, NG-DIMETHYLARGININE DIMETHYLAMINOHYDROLASE 1, CITRULLINE (3 entities in total)
• 機能のキーワード: ddah, hydrolase, nitric oxide synthase inhibitor
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 63993.62

構造登録者

Murray-Rust, J.,O'Hara, B.P.,Rossiter, S.,Leiper, J.M.,Vallance, P.,McDonald, N.Q. (登録日: 2006-11-29, 公開日: 2007-02-13, 最終更新日: 2024-11-06)

主引用文献

Leiper, J.,Nandi, M.,Torondel, B.,Murray-Rust, J.,Malaki, M.,O'Hara, B.,Rossiter, S.,Anthony, S.,Madhani, M.,Selwood, D.,Smith, C.,Wojciak-Stothard, B.,Rudiger, A.,Stidwill, R.,McDonald, N.Q.,Vallance, P.
Disruption of methylarginine metabolism impairs vascular homeostasis.
Nat. Med., 13:198-203, 2007

PubMed Abstract: Asymmetric dimethylarginine (ADMA) and monomethyl arginine (L-NMMA) are endogenously produced amino acids that inhibit all three isoforms of nitric oxide synthase (NOS). ADMA accumulates in various disease states, including renal failure, diabetes and pulmonary hypertension, and its concentration in plasma is strongly predictive of premature cardiovascular disease and death. Both L-NMMA and ADMA are eliminated largely through active metabolism by dimethylarginine dimethylaminohydrolase (DDAH) and thus DDAH dysfunction may be a crucial unifying feature of increased cardiovascular risk. However, despite considerable interest in this pathway and in the role of ADMA as a cardiovascular risk factor, there is little evidence to support a causal role of ADMA in pathophysiology. Here we reveal the structure of human DDAH-1 and probe the function of DDAH-1 both by deleting the DDAH1 gene in mice and by using DDAH-specific inhibitors which, as we demonstrate by crystallography, bind to the active site of human DDAH-1. We show that loss of DDAH-1 activity leads to accumulation of ADMA and reduction in NO signaling. This in turn causes vascular pathophysiology, including endothelial dysfunction, increased systemic vascular resistance and elevated systemic and pulmonary blood pressure. Our results also suggest that DDAH inhibition could be harnessed therapeutically to reduce the vascular collapse associated with sepsis.

PubMed: 17273169
DOI: 10.1038/nm1543

実験手法

X-RAY DIFFRACTION (2.3 Å)