DDAH2

Official Full Name

DDAH family member 2, ADMA-independent

Organism

Homo sapiens

GeneID

23564

Background

This gene encodes a dimethylarginine dimethylaminohydrolase. The encoded enzyme functions in nitric oxide generation by regulating the cellular concentrations of methylarginines, which in turn inhibit nitric oxide synthase activity. The protein may be localized to the mitochondria. Alternative splicing resulting in multiple transcript variants. [provided by RefSeq, Dec 2014]

Synonyms

G6a; DDAH; NG30; DDAHII; HEL-S-277;

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Detailed Information

Dimethylarginine dimethylaminohydrolase 2 (DDAH2) is an enzyme that plays a crucial role in the metabolism of arginine, an essential amino acid required for various physiological functions. The DDAH2 gene encodes for this enzyme, which is primarily expressed in the liver and kidneys.

Structure And Function of DDAH2

The DDAH2 enzyme is a member of the amidohydrolase superfamily, and its primary function is the metabolism of dimethylarginine (DMA). It catalyzes the conversion of DMA to guanidine and dimethylamine, which are then excreted in the urine. The structure of DDAH2 enzyme is characterized by a conserved catalytic core, which is similar to other members of the amidohydrolase family. The enzyme consists of two domains, an N-terminal domain responsible for substrate binding and a C-terminal domain involved in catalysis.

Regulation of DDAH2 Expression

The expression of DDAH2 is regulated at the transcriptional and post-transcriptional levels. Transcription factors, such as nuclear factor kappa B (NF-κB) and activating transcription factor 2 (ATF2), have been shown to regulate the expression of DDAH2 in response to various stimuli. Post-transcriptional regulation occurs through RNA binding proteins, such as heterogeneous nuclear ribonucleoprotein A1 (HNRNP A1), which have been shown to interact with the DDAH2 mRNA and modulate its stability.

Association of DDAH2 with Diseases

Several studies have shown that DDAH2 is associated with various pathological conditions. Increased expression of DDAH2 has been observed in conditions such as liver cirrhosis, hepatocellular carcinoma, and renal failure. In these diseases, the increased expression of DDAH2 is thought to be a compensatory mechanism to counteract the increased levels of dimethylarginine, which has been associated with poor prognosis in these conditions.

Role of DDAH2 in Cardiovascular Diseases

Dimethylarginine has been shown to be a biomarker of cardiovascular diseases, and its metabolism by DDAH2 is crucial for maintaining cardiovascular homeostasis. Decreased expression of DDAH2 has been observed in patients with cardiovascular diseases, leading to increased levels of dimethylarginine, which has been associated with atherosclerosis, hypertension, and heart failure. Inhibition of DDAH2 has also been shown to promote vascular smooth muscle cell proliferation and migration, which contribute to the pathogenesis of atherosclerosis.

Role of DDAH2 in Neurological Disorders

Increased levels of dimethylarginine have been observed in patients with neurological disorders such as Alzheimer's disease and multiple sclerosis. In these conditions, the increased levels of dimethylarginine are thought to contribute to the pathophysiology of the disease by promoting oxidative stress, inflammation, and neurodegeneration. Inhibition of DDAH2 has been shown to attenuate the progression of these diseases in animal models.

Therapeutic Potential of DDAH2 Inhibition

Given the association of DDAH2 with various diseases, its inhibition has been proposed as a potential therapeutic target. several small molecule inhibitors of DDAH2 have been developed and are currently undergoing clinical trials. These inhibitors have shown potential in reducing the progression of cardiovascular diseases, neurological disorders, and liver disease.

References:

Lambden, Simon et al. "Dimethylarginine dimethylaminohydrolase 2 regulates nitric oxide synthesis and hemodynamics and determines outcome in polymicrobial sepsis." Arteriosclerosis, thrombosis, and vascular biology vol. 35,6 (2015): 1382-92. doi:10.1161/ATVBAHA.115.305278
Lange, Clemens et al. "Dimethylarginine dimethylaminohydrolase-2 deficiency promotes vascular regeneration and attenuates pathological angiogenesis." Experimental eye research vol. 147 (2016): 148-155. doi:10.1016/j.exer.2016.05.007

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