Protein detoxification

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Protein detoxification is the process by which proteins containing methylated arginine are broken down and removed from the body.

Contents

Arginine (Arg) is a non-essential amino acid 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 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 dimethylarginine dimethylaminohydrolase (DDAH). Impairment of DDAH function slows breakdown and increases the level of toxic asymmetrically methylated arginine forms. [1]
Long term exposure to these toxic amino acids is associated with endothelial dysfunction, arterial stiffness, insulin resistance, chronic kidney disease, heart disease, dementia and ageing. [2] [3] [4]

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.
Protein detoxification pathway. Protein detoxification pathway.jpg
Protein detoxification pathway.

History

In 1970, it was demonstrated that protein turnover releases the free methylated arginine derivatives:

  1. asymmetric dimethylarginine (ADMA),
  2. methylarginine, (also referred to as N-methyl-L-arginine, N-monomethylargine or L-NMMA), and
  3. symmetrical dimethylarginine (SDMA). [5]

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). [6] Then, in 1996 MacAllister at St George's Hospital Medical School in London, recognised that inhibiting the enzyme DDAH increases intracellular concentrations of ADMA. [7] 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 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 and RNA processing. [8]

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. [9]

Around 60 mg of ADMA is produced per day. [10] 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. [11]

PRMTs

Protein arginine methyltransferase's (PRMTs) are activated by shear stress [12] and LDL cholesterol. [13] Two types of PMRTs have been characterised.

Type 1 PRMTs 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. [14]

DDAH

Dimethylarginine dimethylaminohydrolase (DDAH) activity is inhibited by NO, reactive oxygen species (ROS) and L-arginine. [15]

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. 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 and estradiol and inhibited by hypoxia, hyperglycaemia and LPS. [16]

Role in disease

Asymmetrically methylated arginine forms (AMAF) inhibit nitric oxide synthase and the formation of nitric oxide (NO), also known as 'endothelium-derived relaxing factor', 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. 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. [17]

Long-standing arterial stiffness inevitably leads to heart failure, kidney failure and dementia; 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.

Endothelium.jpg
Vascular endothelium
Pulsatile flow.jpg
Shear stress in micro-circulation as a result of arterial stiffness
Endothelial dysfunction associated inhibtion of eNOS, reduced NO and vasoconstriction is associated with arterial stiffness. Increased pulse pressure drives arterial pulsations further down the arterial tree, increasing shear stress.

Aging

When William Osler stated that “man is as old as his arteries” he referred to arterial stiffening, a condition now acknowledged as an integrated biomarker of ageing. [18]

Preservation of the arterial tree 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.

Related Research Articles

Arginine Amino acid

Arginine, also known as l-arginine (symbol Arg or R), is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, an α-carboxylic acid group, and a side chain consisting of a 3-carbon aliphatic straight chain ending in a guanidino group. At physiological pH, the carboxylic acid is deprotonated (−COO−), the amino group is protonated (−NH3+), and the guanidino group is also protonated to give the guanidinium form (-C-(NH2)2+), making arginine a charged, aliphatic amino acid. It is the precursor for the biosynthesis of nitric oxide. It is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG.

In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms are commonly used in chemistry, biochemistry, soil science, and the biological sciences.

Citrulline Chemical compound

The organic compound citrulline is an α-amino acid. Its name is derived from citrullus, the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in 1914 by Japanese researchers Yotaro Koga and Ryo Odake and further codified by Mitsunori Wada of Tokyo Imperial University in 1930. It has the formula H2NC(O)NH(CH2)3CH(NH2)CO2H. It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia by converting it into urea. Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide from the amino acid arginine, catalyzed by nitric oxide synthase.

Histone methyltransferase

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

Endothelium Cells that line the Inner surface of blood vessels

Endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels, and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Nitric oxide synthase

Nitric oxide synthases (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS and nNOS. The inducible isoform, iNOS, involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease.

Tetrahydrobiopterin

Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide syntheses. Chemically, its structure is that of a (dihydropteridine reductase) reduced pteridine derivative (Quinonoid dihydrobiopterin).

Mevastatin

Mevastatin is a hypolipidemic agent that belongs to the statins class.

Argininosuccinate synthase

Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.

Asymmetric dimethylarginine Chemical compound

Asymmetric dimethylarginine (ADMA) 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 interferes with L-arginine in the production of nitric oxide (NO), a key chemical involved in normal endothelial function and, by extension, cardiovascular health.

CARM1

CARM1, also known as PRMT4, is an enzyme encoded by the CARM1 gene found in human beings, as well as many other mammals. It has a polypeptide (L) chain type that is 348 residues long, and is made up of alpha helices and beta sheets. Its main function includes catalyzing the transfer of a methyl group from S-Adenosyl methionine to the side chain nitrogens of arginine residues within proteins to form methylated arginine derivatives and S-Adenosyl-L-homocysteine. CARM1 is a secondary coactivator through its association with p160 family of coactivators. It is responsible for moving cells toward the inner cell mass in developing blastocysts.

Endothelial NOS

Endothelial NOS (eNOS), also known as nitric oxide synthase 3 (NOS3) or constitutive NOS (cNOS), is an enzyme that in humans is encoded by the NOS3 gene located in the 7q35-7q36 region of chromosome 7. This enzyme is one of three isoforms that synthesize nitric oxide (NO), a small gaseous and lipophilic molecule that participates in several biological processes. The other isoforms include neuronal nitric oxide synthase (nNOS), which is constitutively expressed in specific neurons of the brain and inducible nitric oxide synthase (iNOS), whose expression is typically induced in inflammatory diseases. eNOS is primarily responsible for the generation of NO in the vascular endothelium, a monolayer of flat cells lining the interior surface of blood vessels, at the interface between circulating blood in the lumen and the remainder of the vessel wall. NO produced by eNOS in the vascular endothelium plays crucial roles in regulating vascular tone, cellular proliferation, leukocyte adhesion, and platelet aggregation. Therefore, a functional eNOS is essential for a healthy cardiovascular system.

PRMT1

Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the PRMT1 gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.

Dimethylargininase

In the field of enzymology, a dimethylargininase, also known as a dimethylarginine dimethylaminohydrolase (DDAH), is an enzyme that catalyzes the chemical reaction:

Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension. It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.

Nitric oxide is a molecule and chemical compound with chemical formula of NO. In mammals including humans, nitric oxide is a signaling molecule involved in many physiological and pathological processes. It is a powerful vasodilator with a half-life of a few seconds in the blood. Standard pharmaceuticals such as nitroglycerine and amyl nitrite are precursors to nitric oxide. Low levels of nitric oxide production are typically due to ischemic damage in the liver.

Methylarginine Chemical compound

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.

Arsenic biochemistry refers to biochemical processes that can use arsenic or its compounds, such as arsenate. Arsenic is a moderately abundant element in Earth's crust, and although many arsenic compounds are often considered highly toxic to most life, a wide variety of organoarsenic compounds are produced biologically and various organic and inorganic arsenic compounds are metabolized by numerous organisms. This pattern is general for other related elements, including selenium, which can exhibit both beneficial and deleterious effects. Arsenic biochemistry has become topical since many toxic arsenic compounds are found in some aquifers, potentially affecting many millions of people via biochemical processes.

Gaseous signaling molecules are gaseous molecules that are either synthesised internally (endogenously) in the organism, tissue or cell or are received by the organism, tissue or cell from outside and that are used to transmit chemical signals which induce certain physiological or biochemical changes in the organism, tissue or cell. The term is applied to, for example, oxygen, carbon dioxide, nitric oxide, carbon monoxide, hydrogen sulfide, sulfur dioxide, nitrous oxide, hydrogen cyanide, ammonia, methane, hydrogen, ethylene, etc.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

References

  1. ↑ Ito, A. Novel Mechanism for Endothelial Dysfunction: Dysregulation of Dimethylarginine Dimethylaminohydrolase Circulation 1999;99;3092-3095
  2. ↑ Boger, R. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor Cardiovascular Research 2003;59:824–833
  3. ↑ Palm, F. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol 2007;293:H3227–H3245
  4. ↑ Kielstein, J. Asymmetric Dimethylarginine: A Cardiovascular Risk Factor and a Uremic Toxin Coming of Age? Archived 2011-07-13 at the Wayback Machine Am J Kidney Dis. 2005;46:186-202
  5. ↑ Kakimoto, Y. Isolation and identification of N,N and N,N-Dimethyl-arginine, N-mono-, and Trimethyllysine, and Glucosylgalactosyl-, and Galactosyl-δ-hydroxylysine from human urine J Biol Chem 1970;245: 5751-5758
  6. ↑ Vallance, P. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure Lancet 1992;339(8793):572-5
  7. ↑ MacAllister, R. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase Br J Pharmacol 1996;119(8):1533-40
  8. ↑ Bedford, M. Arginine Methylation: Review: An Emerging Regulator of Protein Function Archived 2011-07-21 at the Wayback Machine Molecular Cell 2005;18:263–272
  9. ↑ Masuda, H. Accumulated endogenous NOS inhibitors, decreased NOS activity, and impaired cavernosal relaxation with ischemia Am J Physiol Regulatory Integrative Comp Physiol 282: R1730–R1738, 2002
  10. ↑ Achan, V. Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase Arterioscler Thromb Vasc Biol 2003;23:1455-1459
  11. ↑ Cooke, P. DDAH: A target for vascular therapy? Vasc Med 2010;15;235-238
  12. ↑ Osanai, T. Effect of Shear Stress on Asymmetric Dimethylarginine Release From Vascular Endothelial Cells Hypertension 2003;42:985–90
  13. ↑ Böger, R. LDL Cholesterol Upregulates Synthesis of Asymmetrical Dimethylarginine in Human Endothelial Cells Circ Res 2000;87:99–105
  14. ↑ Anthony, S. Endogenous production of nitric oxide synthase inhibitors Vascular Medicine 2005; 10: S3–9
  15. ↑ Palm, F. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems AJP Heart Circ Physiol 2007;293:H3227–H3245
  16. ↑ Blackwell, S. The biochemistry, measurement and current clinical significance of asymmetric dimethylarginine Ann Clin Biochem 2010;47:17–28
  17. ↑ Zakrzewicz, D. From arginine methylation to ADMA: A novel mechanism with therapeutic potential in chronic lung diseases Pulmonary Medicine 2009;9:1471-2466
  18. ↑ Osler, W. The Principles and Practice of Medicine. 3rd edition. New York, NY: Appleton 1892
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