One More Important ADMA Relationship

As you can easily see from the above diagrams, the structure of arginine (above) and asymmetric dimethyarginine (below) are identical except that on the left side asymmetric dimethyarginine (ADMA) has two methyl groups (CH₃) attached to nitrogen (N) instead of the two hydrogen atoms attached to nitrogen in arginine. This very similar chemical structure is critical to the precision functions of ADMA in human disease.

We have already discussed how asymmetric dimethylarginine is also very much alike metformin in its chemical structure. That similarity accounts for the fact that metformin blocks the effect of ADMA in activating the nutrient sensing mechanism to increase mTOR master genetic metabolic growth switch activity and decrease AMPK master genetic metabolic survival switch activity. Arginine is an amino acid building block for proteins including the proteins that surround genes to keep them tightly wound up and inactive. ADMA is formed when the arginine in those proteins around genes has methyl groups (CH₃) added as part of the process of unwinding the DNA in the gene to expose it and activate the gene. When the work of gene activation is done, the proteins are broken down into their amino acid components and ADMA enters the circulation and cell fluid. ADMA can then function as a signaling molecule itself and it changes the activity of more than 50 genes. As a reminder of how ADMA and metformin structure are so similar, see the diagram below. In health, ADMA is part of gene regulation that helps to form a fetus and child. Later in life, higher levels of ADMA are produced as the result of gene reactivation that causes disease.

That information about ADMA sets us up for the way that most clinicians think about this molecule. In normal healthy humans, there is an enzyme in the inner wall of the artery that is critical to arterial health. It is called endothelial nitric oxide synthase (eNOS). This enzyme converts arginine to nitric oxide that is vital to arterial health. Nitric oxide is important to help the artery dilate in response to exercise. If nitric oxide is not available, the artery may actually contract in response to increased demand and reduce block flow. In healthy humans, eNOS converts arginine to beneficial nitric oxide. If ADMA levels are elevated, ADMA causes eNOS to produce oxidants instead of beneficial nitric oxide. Increased ADMA causes increased oxidant production which is very detrimental to arterial health while reducing nitric oxide production which is so beneficial to the health of arteries. Nitric oxide is the active ingredient in nitroglycerin tablets which dilate the artery to relieve chest pain in angina.

Virtually all the science has been focused on this part of the ADMA story. Prominent scientists from Stanford tried to influence this relationship between eNOS and ADMA by giving arginine supplements and so forth, but these efforts did not turn out to be beneficial. It does not make sense that metformin has direct benefit in this competition at the level of eNOS. A competitive inhibitor of ADMA would not block the competitive inhibition of arginine conversion to nitric oxide by ADMA. It works by blocking ADMA effects at the nutrient sensor that regulates mTOR and AMPK. This evidence points to ADMA as one of the most fascinating and important molecules in human health and biology. In the fetus and child, ADMA is a product of gene regulation that is critical to normal development. In older adults, ADMA levels are also a marker for increased gene activity, but in that case ADMA increased oxidant production and it is detrimental. Blocking the effects of ADMA is a precision intervention that attacks one of the root causes of chronic disease.