L-Homocitrulline is an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

and can be detected in larger amounts in the

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

of individuals with

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

cycle disorders. At present, it is thought that the depletion of the

ornithine Ornithine is a non-proteinogenic α-amino acid that plays a role in the urea cycle. It is not incorporated into proteins during translation. Ornithine is abnormally accumulated in the body in ornithine transcarbamylase deficiency, a disorder of th ...

supply causes the accumulation of carbamyl-phosphate in the urea cycle which may be responsible for the enhanced synthesis of homocitrulline and

homoarginine Homoarginine is an nonproteinogenic alpha-amino acid. It is structurally equivalent to a one-methylene group-higher homolog of arginine and to the guanidino derivative of lysine. L-Homoarginine is the naturally-occurring enantiomer. Physiologica ...

. Both amino acids can be detected in urine. Amino acid analysis allows for the quantitative analysis of these amino acid metabolites in biological fluids such as urine or

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood is com ...

Description

Homocitrulline is one methylene group longer than

citrulline 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 ...

, but similar in structure. The metabolite is generated from a lysine residue after

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

reacts with

cyanate The cyanate ion is an anion with the chemical formula . It is a resonance of three forms: (61%) ↔ (30%) ↔ (4%). Cyanate is the derived anion of isocyanic acid, H−N=C=O, and its lesser tautomer cyanic acid (a.k.a. cyanol), H−O−C� ...

. Cyanate is present in the human body in equilibrium with urea. Under physiological conditions the urea concentration may be too low to allow extensive carbamylation. However, the conversion process leading to the formation of homocitrulline from lysine in proteins is known to occur in vivo. During

renal failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

conditions, the urea concentration increases and carbamylation of many proteins can occur, which can be detected. It is believed that most

carbamylation Isocyanic acid is a chemical compound with the structural formula HNCO, which is often written as . It is a colourless, Volatility (chemistry), volatile and poisonous gas, boiling point, condensing at 23.5 °C. It is the predominant tautome ...

takes place during inflammation when the enzyme

myeloperoxidase Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the ''MPO'' gene on chromosome 17. MPO is most abundantly expressed in neutrophils (a subtype of white blood cells), and produces hypohalous acids to carry out their anti ...

is released from

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

s. This enzyme converts

thiocyanate Thiocyanates are salts containing the thiocyanate anion (also known as rhodanide or rhodanate). is the conjugate base of thiocyanic acid. Common salts include the colourless salts potassium thiocyanate and sodium thiocyanate. Mercury(II) t ...

to cyanate. Increased levels of cyanate can now carbamylate lysine residues. Carbamylation

Myeloperoxidase released from neutrophils converts thiocyanate to cyanate which carbamylates lysine residues to form homocitrulline. Thiocyanate (SCN⁻) is a naturally occurring pseudohalide found in dietary sources. Myeloperoxidase can use SCN⁻ as a cosubstrate together with

hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscosity, viscous than Properties of water, water. It is used as an oxidizer, bleaching agent, and antiseptic, usua ...

(H₂O₂) to form cyanate. In patients with

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

dysfunction urea is elevated. Urea is in equilibrium with cyanate and isocyanate. Carbamylation of nucleophilic amino groups, for example lysine residues, can modify protein structures and ultimately cause metabolic dysfunctions.

In diseases

Homocitrulline has been suggested as a confounding antigen for

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

antibodies targeting citrullinated proteins/peptides. Antibodies binding to homocitrulline-containing sequences have been found in rheumatoid arthritis patients' sera More recently, it has been shown that homocitrulline-containing proteins are present in rheumatoid arthritis (RA) joints.Turunen S, Koivula MK, Melkko J, Alasaarela E, Lehenkari P, Risteli J. Different amounts of protein-bound citrulline and homocitrulline in foot joint tissues of a patient with anti-citrullinated protein antibody positive erosive rheumatoid arthritis. J Transl Med. 2013; 11:224 In rodents they may affect T-cell triggering and possibly autoantibody formation, and possibly also in humans. In another metabolic disorder, in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, first described in 1969, ornithine levels maybe elevated five to ten times in comparison to normal levels. In addition, in this syndrome, levels of

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...

orotic acid Orotic acid () is a pyrimidinedione and a carboxylic acid. Historically, it was believed to be part of the vitamin B complex and was called vitamin B13, but it is now known that it is not a vitamin. The compound is synthesized in the body via ...

and homocitrulline may be elevated as well. In people with

hyperammonemia Hyperammonemia, or high ammonia levels, is a metabolic disturbance characterised by an excess of ammonia in the blood. Severe hyperammonemia is a dangerous condition that may lead to brain injury and death. It may be primary or secondary. Ammoni ...

orotic acid and homocitrulline appear to be chronically elevated after a high protein diet, but may be normal when fasting. The metabolic disorder, lysinuric protein intolerance is caused by the body's inability to digest and use certain protein building blocks or amino acids. These are lysine,

arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...

, and ornithine. These amino acids are found in many protein-rich foods. Since in this disorder the human body cannot effectively break down these amino acids people typically experience

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and vomiting after ingesting protein rich foods. Associated features of this protein intolerance may include an enlarged liver and

spleen The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The spleen plays important roles in reg ...

, short stature, muscle weakness, impaired immune function, and progressively

brittle bones Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be m ...

that are prone to fracture and a lung disorder called

pulmonary alveolar proteinosis Pulmonary alveolar proteinosis (PAP) is a rare lung disorder characterized by an abnormal accumulation of surfactant-derived lipoprotein compounds within the alveoli of the lung. The accumulated substances interfere with the normal gas exchange an ...

may also develop. In addition, the accumulation of amino acids in the kidneys can cause

end-stage renal disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

(ESRD). In ESRD the kidneys are no longer able to filter fluids and waste products from the body effectively.

References

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Bibliography

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