Sample Newsletter February 2005

Arginine, Nitric Oxide and Mental Deficiency

Tom Stockdale

Arginine is not usually considered to be an essential amino acid other than for certain rapidly growing adolescents who require it as a constituent for their expanding tissues.  The urea we excrete is released from arginine by an enzyme which is only present in the liver, but the source of this arginine is the kidneys where it is synthesised from ammonia, which is derived from surplus amino acids in the diet.

Arginine is also synthesised in other tissues where some is used to produce creatine phosphate, a source of energy for muscles in the instant before the rate of ATP synthesis increases in response to stimulation.  Quite the most interesting use of arginine is for nitric acid (NO) synthesis in brain tissue.  All the functions of NO do not appear to have been identified, but it is known that a compound referred to as cGMP cannot be synthesised without the use of NO as a co-factor.  cGMP is used as the gatekeeper which regulates the size of each tiny pulse of calcium ions (Ca²⁺), which enters nerve cells after a neurotransmitter has crossed a synapse and momentarily combined with an appropriate receptor on an efferent neuron.  Thus, a decrease in the supply of cGMP caused by failure to synthesise sufficient arginine enables additional Ca²⁺ to enter cells.  Because increases in intracellular Ca^2+, stimulate ATP synthesis, its increase carries with it the potential to induce hyperactivity, mania and encephalopathy when inadequately regulated.

Calcium ions can alter the way in which proteins fold and the manner in which enzymes operate and it is quite possible that the amyloid plaques, associated with Alzheimer’s disease, and the production of prion protein associated with BSE, are not so much the causes of these diseases but symptomatic of the loss of control over intracellular Ca²⁺ concentration.  Full control over the influx of Ca²⁺ into cells depends upon the presence of sufficient folic acid and vitamins B₁, B₃, B₆ and B₁₂, but their outflux requires sufficient iodine, selenium and vitamin B₃.  Because much of the latter is synthesised endogenously from tryptophan an adequate supply of this amino acid is essential.

Much of the arginine in brain tissue is synthesised from the branch chain amino acids, valine, leucine and isoleucine in a reaction needing thiamine and niacin (vitamins B₁ and B₃).  The importance of this reaction is emphasised by beri-beri being caused by thiamine deficiency and pellagra being caused by niacin deficiency, and by both diseases involving mental deficiency.  From the above it can be deduced that diseases such as manic depression, multiple sclerosis and vCJD, which usually first become manifest in adolescents or young adults, are at least in part, caused by arginine deficiency and consumption of low protein diets. Even when symptoms appear later in life, their probable cause is the loss of neurons, following some kind of traumatic experience at an early age, which was associated with an insufficient intake of protein and an increased rate of gluconeogenesis.

Surprisingly, there are three different forms of the NO synthesase enzyme.  Not only does each function best in slightly different physiological conditions, but more than one can be present at one time in a single cell.  By enabling accurate regulation of intracellular Ca²⁺ concentration, this enables neurons to produce more dendrites and therefore to be able to communicate with more neighbouring neurons than would otherwise be the case.  This suggests that the circumstances which enabled three forms of NO synthesase to become established in the human genome, are also those which enabled Homo sapiens to become the predominant species.  The question arises how many other species have more than one form of NO synthesase?

References