Protein detoxification
Encyclopedia
Protein detoxification is the process by which proteins containing methylated
Methyl group
Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

 arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

 are broken down and removed from the body.
Arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

 (Arg) is a non-essential amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 and one of the most commonly occurring natural amino acids. Methylated arginine is a modified version of arginine that is commonly formed from protein arginine (arginine incorporated in protein). Asymmetrically
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 methylated forms of arginine are toxic when released during protein turnover.

The protein detoxification pathway eliminates free methylated-arginine derivatives from the cell. Symmetrically methylated forms are not toxic and are excreted unchanged by the kidney. Asymmetrically methylated forms however are toxic and must first be broken down. This step requires the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 dimethylarginine dimethylaminohydrolase (DDAH). Impairment of DDAH function slows breakdown and increases the level of toxic asymmetrically methylated arginine forms .

Long term exposure to these toxic amino acids is associated with endothelial dysfunction
Endothelial dysfunction
Endothelial dysfunction is a systemic pathological state of the endothelium and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by the endothelium...

, arterial stiffness
Arterial stiffness
Arteries stiffen as a consequence of age and arteriosclerosis. Age related stiffness occurs when the elastic fibres within the arterial wall begin to fray due to mechanical stress. The two leading causes of death in the developed world, myocardial infarction and stroke, are both a direct...

, insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...

, chronic kidney disease, heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...

, dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

 and ageing
Ageing
Ageing or aging is the accumulation of changes in a person over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline...

.


Therapeutic strategies that target the protein detoxification pathway aim to:
  • reduce intracellular levels of free asymmetrically methylated arginine derivatives,
  • slow the ageing process
  • delay the development of disorders associated with ageing.

History

In 1970, it was demonstrated that protein turnover releases the free methylated arginine derivatives:
  1. asymmetric dimethylarginine
    Asymmetric dimethylarginine
    Asymmetric dimethylarginine is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally-essential amino acid...

     (ADMA),
  2. methylarginine
    Methylarginine
    N-Methylarginine is an inhibitor of nitric oxide synthase. Chemically, it is a methyl derivative of the amino acid arginine. It is used as a biochemical tool in the study of physiological role of nitric oxide....

    , (also referred to as N-methyl-L-arginine, N-monomethylargine or L-NMMA), and
  3. symmetrical dimethylarginine (SDMA).


The potential toxicity of the two asymmetrically methylated amino acids however was not fully appreciated until 1992 when Patrick Vallance and his London co-workers at the Wellcome Research Laboratories demonstrated that ADMA inhibits nitric oxide synthase (NOS). Then, in 1996 MacAllister at St George's Hospital Medical School in London, recognised that inhibiting the enzyme DDAH increases intracellular concentrations of ADMA. To describe the process of protein turnover, the elimination of free methylated arginine derivatives and the catabolism of the two asymmetrically methylated arginine derivatives ADMA and L-NMMA, the Australian physician Trevor Tingate coined the term protein detoxification in 2010.

Synthesis and clearance

Protein arginine methylation
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...

 occurs posttranslationally and is catalysed by protein arginine methyltransferase (PRMT). No direct synthesis of methylated arginine derivatives occurs from the free amino acid. The methylation of protein arginine plays an important role in the regulation of many cell processes including gene transcription, cell signal transduction, DNA repair
DNA repair
DNA repair refers to a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1...

 and RNA processing.

During protein turnover three arginine methylated derivatives are released: L-NMMA, SDMA and ADMA.
SDMA is not directly toxic and is eliminated unchanged by renal excretion.
L-NMMA and ADMA however, are both potent inhibitors of NOS.


Around 60 mg of ADMA is produced per day. Unlike SDMA, 80% of ADMA and NMMA is catabolised by the enzyme DDAH. The activity of DDAH is therefore an important determinant of ADMA and NMMA levels, and thus NOS activity.

PRMTs

Protein arginine methyltransferase's (PRMTs) are activated by shear stress
Shear stress
A shear stress, denoted \tau\, , is defined as the component of stress coplanar with a material cross section. Shear stress arises from the force vector component parallel to the cross section...

 and LDL cholesterol. Two types of PMRTs have been characterised.
Type 1 PMRTs are found mainly in endothelial and smooth muscle cells and produce methylated proteins containing ADMA and L-NMMA.
Type 2 PRMTs produce proteins that contain SDMA and L-NMMA.

DDAH

Dimethylarginine dimethylaminohydrolase (DDAH) activity is inhibited by NO
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

, reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 (ROS) and L-arginine.

Two isoforms of DDAH have been identified.
DDAH-1 is found in tissues expressing neuronal NOS (nNOS) and in the liver, kidney and lung. Expression is increased by IL-1β and inhibited by oxLDL and TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...

. Plasma levels of ADMA reflect DDAH-1 activity.

DDAH-2 is found in tissues expressing endothelial NOS (eNOS) and inducible NOS (iNOS). Expression is increased by NADPHox, all trans retinoic acid, pioglitazone
Pioglitazone
Pioglitazone is a prescription drug of the class thiazolidinedione with hypoglycemic action.Pioglitazone is marketed as trademarks Actos in the USA, Canada, the UK and Germany, Glustin in Europe,"Glizone" and "Pioz" in India by Zydus CND and USV respectively and Zactos in Mexico by Takeda...

 and estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...

 and inhibited by hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

, hyperglycaemia and LPS
LPS
LPS can stand for more than one thing:* Lipopolysaccharide * Liters per second* Low Pressure Sodium vapor lamps* Leases per second, a speed measure for DHCP servers* Leica Photogrammetry Suite, official name was changed to "LPS" in 2008...

.

Role in disease

Asymmetrically methylated arginine forms (AMAF) inhibit nitric oxide synthase and the formation of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 (NO), also known as 'endothelium-derived relaxing factor
Endothelium-derived relaxing factor
Endothelium-derived relaxing factor is produced and released by the endothelium to promote smooth muscle relaxation. The best-characterized is nitric oxide . Some sources equate EDRF and nitric oxide....

', or 'EDRF'. Nitric oxide is critical to blood vessel function and inhibition leads to an increase in arterial stiffness due to vasoconstriction. Indeed, by protecting the vessel against vasoconstriction nitric oxide has been referred to as the fountain of youth
Fountain of Youth
The Fountain of Youth is a legendary spring that reputedly restores the youth of anyone who drinks of its waters. Tales of such a fountain have been recounted across the world for thousands of years, appearing in writings by Herodotus, the Alexander romance, and the stories of Prester John...

. It also protects blood vessels by inhibiting platelet activation, smooth muscle proliferation and endothelial cell activation.

Reduced arterial stiffness protects the heart. Asymmetrically methylated arginine forms by contrast inhibit NOS, reduce nitric oxide and increase central arterial pressure .

Long-standing arterial stiffness
Arterial stiffness
Arteries stiffen as a consequence of age and arteriosclerosis. Age related stiffness occurs when the elastic fibres within the arterial wall begin to fray due to mechanical stress. The two leading causes of death in the developed world, myocardial infarction and stroke, are both a direct...

 inevitably leads to heart failure, kidney failure and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...

; the three leading causes of death in later years. Protein detoxification removes free methylarginines that would otherwise inhibit the generation of nitric oxide. The pathway is an important determinant of the speed by which diseases of ageing will ultimately manifest.

Aging

When William Osler
William Osler
Sir William Osler, 1st Baronet was a physician. He was one of the "Big Four" founding professors at Johns Hopkins Hospital as the first Professor of Medicine and founder of the Medical Service there. Sir William Osler, 1st Baronet (July 12, 1849 – December 29, 1919) was a physician. He was...

 stated that “man is as old as his arteries” he referred to arterial stiffening
Arterial stiffness
Arteries stiffen as a consequence of age and arteriosclerosis. Age related stiffness occurs when the elastic fibres within the arterial wall begin to fray due to mechanical stress. The two leading causes of death in the developed world, myocardial infarction and stroke, are both a direct...

, a condition now acknowledged as a integrated bio-marker of ageing.

Preservation of the arterial tree
Arterial tree
In anatomy, arterial tree is used to refer to all arteries and/or the branching pattern of the arteries. This article regards the human arterial tree. Starting from the aorta:- Ascending aorta :In anatomy, arterial tree is used to refer to all arteries and/or the branching pattern of the arteries....

in a relaxed and elastic state is core doctrum of anti-ageing medicine. The recognition of free methylarginine derivatives as toxins that accelerate ageing by inhibiting the production of nitric oxide focuses on the importance of maintaining the protein detoxification pathway.

This can be achieved by a combination of dietary, behavioural and therapeutic interventions.
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