Hawkinsinuria

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Hawkinsinuria
Other names4-Alpha-hydroxyphenylpyruvate hydroxylase deficiency
Hawkinsin.png
Hawkinsin
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Hawkinsinuria is an autosomal dominant metabolic disorder affecting the metabolism of tyrosine. [1] [2]

Contents

Normally, the breakdown of the amino acid tyrosine involves the conversion of 4-hydroxyphenylpyruvate to homogentisate by 4-hydroxyphenylpyruvate dioxygenase. Complete deficiency of this enzyme would lead to tyrosinemia III. In rare cases, however, the enzyme is still able to produce the reactive intermediate 1,2-epoxyphenyl acetic acid, but is unable to convert this intermediate to homogentisate. The intermediate then spontaneously reacts with glutathione to form 2-L-cystein-S-yl-1,4-dihydroxy-cyclohex-5-en-1-yl acetic acid (hawkinsin). [3] [4]

Patients present with metabolic acidosis during the first year of life, and growth arrest around the time of weaning off breast milk. Treatment involves a diet containing a low amount of phenylalanine and tyrosine. Tolerance toward these amino acids normalizes as the patients get older. Then only a chlorine-like smell of the urine indicates the presence of the condition. Patients have a normal life and do not require treatment or a special diet. [4]

The production of hawkinsin is the result of a gain-of-function mutation. Inheritance of hawkinsinuria is therefore autosomal dominant (presence of a single mutated copy of the gene causes the condition). The gene affected is the HPD gene encoding 4-hydroxyphenylpyruvic acid dioxygenase, on chromosome 12q24. [4] It is unusual in that most other inborn errors of metabolism are caused by loss-of-function mutations, and hence have recessive inheritance (condition occurs only if both copies are mutated).[ citation needed ]

See also

Related Research Articles

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L-Tyrosine or tyrosine or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is from the Greek tyrós, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in the protein casein from cheese. It is called tyrosyl when referred to as a functional group or side chain. While tyrosine is generally classified as a hydrophobic amino acid, it is more hydrophilic than phenylalanine. It is encoded by the codons UAC and UAU in messenger RNA.

<span class="mw-page-title-main">Alkaptonuria</span> Medical condition

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<span class="mw-page-title-main">Maple syrup urine disease</span> Autosomal recessive metabolic disorder

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<span class="mw-page-title-main">Tyrosinemia</span> Medical condition

Tyrosinemia or tyrosinaemia is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms of untreated tyrosinemia include liver and kidney disturbances. Without treatment, tyrosinemia leads to liver failure. Today, tyrosinemia is increasingly detected on newborn screening tests before any symptoms appear. With early and lifelong management involving a low-protein diet, special protein formula, and sometimes medication, people with tyrosinemia develop normally, are healthy, and live normal lives.

<span class="mw-page-title-main">Glycine encephalopathy</span> Medical condition

Glycine encephalopathy is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebrospinal fluid.

<span class="mw-page-title-main">4-Hydroxyphenylpyruvate dioxygenase</span> Fe(II)-containing non-heme oxygenase

4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase, is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydroxyphenylpyruvate into homogentisate. HPPD also catalyzes the conversion of phenylpyruvate to 2-hydroxyphenylacetate and the conversion of α-ketoisocaproate to β-hydroxy β-methylbutyrate. HPPD is an enzyme that is found in nearly all aerobic forms of life.

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<span class="mw-page-title-main">3-Hydroxy-3-methylglutaryl-CoA lyase</span> Class of enzymes

3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

<span class="mw-page-title-main">Homogentisate 1,2-dioxygenase</span> Enzyme

Homogentisate 1,2-dioxygenase (homogentisic acid oxidase, homogentisate oxidase, homogentisicase) is an enzyme which catalyzes the conversion of homogentisate to 4-maleylacetoacetate. Homogentisate 1,2-dioxygenase or HGD is involved in the catabolism of aromatic rings, more specifically in the breakdown of the amino acids tyrosine and phenylalanine. HGD appears in the metabolic pathway of tyrosine and phenylalanine degradation once the molecule homogentisate is produced. Homogentisate reacts with HGD to produce maleylacetoacetate, which then is further used in the metabolic pathway. HGD requires the use of Fe2+ and O2 in order to cleave the aromatic ring of homogentisate.

<span class="mw-page-title-main">Hypermethioninemia</span> Medical condition

Hypermethioninemia is an excess of the amino acid methionine, in the blood. This condition can occur when methionine is not broken down properly in the body.

<span class="mw-page-title-main">4-Hydroxyphenylpyruvic acid</span> Chemical compound

4-Hydroxyphenylpyruvic acid (4-HPPA) is an intermediate in the metabolism of the amino acid phenylalanine. The aromatic side chain of phenylalanine is hydroxylated by the enzyme phenylalanine hydroxylase to form tyrosine. The conversion from tyrosine to 4-HPPA is in turn catalyzed by tyrosine aminotransferase. Additionally, 4-HPPA can be converted to homogentisic acid which is one of the precursors to ochronotic pigment.

<span class="mw-page-title-main">Tyrosine aminotransferase</span> Mammalian protein found in Homo sapiens

Tyrosine aminotransferase is an enzyme present in the liver and catalyzes the conversion of tyrosine to 4-hydroxyphenylpyruvate.

<span class="mw-page-title-main">Fumarylacetoacetate hydrolase</span>

Fumarylacetoacetase is an enzyme that in humans is encoded by the FAH gene located on chromosome 15. The enzyme is involved in the catabolism of the amino acid tyrosine in humans.

<span class="mw-page-title-main">Pyruvate dehydrogenase (lipoamide) alpha 1</span> Protein-coding gene in the species Homo sapiens

Pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial is an enzyme that in humans is encoded by the PDHA1 gene.The pyruvate dehydrogenase complex is a nuclear-encoded mitochondrial matrix multienzyme complex that provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the irreversible conversion of pyruvate into acetyl-CoA. The PDH complex is composed of multiple copies of 3 enzymes: E1 (PDHA1); dihydrolipoyl transacetylase (DLAT) ; and dihydrolipoyl dehydrogenase (DLD). The E1 enzyme is a heterotetramer of 2 alpha and 2 beta subunits. The E1-alpha subunit contains the E1 active site and plays a key role in the function of the PDH complex.

<span class="mw-page-title-main">Maleylacetoacetate isomerase</span> Class of enzymes

In enzymology, maleylacetoacetate isomerase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Tyrosinemia type III</span> Medical condition

Tyrosinemia type III is a rare disorder caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase, encoded by the gene HPD. This enzyme is abundant in the liver, and smaller amounts are found in the kidneys. It is one of a series of enzymes needed to break down tyrosine. Specifically, 4-hydroxyphenylpyruvate dioxygenase converts a tyrosine byproduct called 4-hydroxyphenylpyruvate to homogentisic acid. Characteristic features of type III tyrosinemia include mild mental retardation, seizures, and periodic loss of balance and coordination. Type III tyrosinemia is very rare; only a few cases have been reported.

<span class="mw-page-title-main">Tyrosinemia type I</span> Medical condition

Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe. If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.

<span class="mw-page-title-main">Tyrosine hydroxylase deficiency</span> Medical condition

Tyrosine hydroxylase deficiency (THD) is a disorder caused by disfunction of tyrosine hydroxylase, an enzyme involved in the biosynthesis of dopamine. This condition is one of the causes of dopa-responsive dystonia.

References

  1. Danks, D. M.; Tippett, P; Rogers, J (1975). "A new form of prolonged transient tyrosinemia presenting with severe metabolic acidosis". Acta Paediatr. Scand. 64 (2): 209–214. doi:10.1111/j.1651-2227.1975.tb03823.x. PMID   1130176. S2CID   28981382.
  2. Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F (2000). "Mutations in the 4-hydroxyphenylpyruvic acid dioxygenase gene are responsible for tyrosinemia type III and hawkinsinuria". Mol Genet Metab. 71 (3): 506–510. doi:10.1006/mgme.2000.3085. PMID   11073718.
  3. Niederwieser, A.; Matasovic, A.; Tippett, P.; Danks, D.M. (1977). "A new sulfur amino acid, named Hawkinsin, identified in a baby with transient tyrosinemia and her mother". Clin. Chim. Acta. 76 (3): 345–356. doi:10.1016/0009-8981(77)90161-9. PMID   858207.
  4. 1 2 3 McKusick, Victor A.; Stumpf, Anne M. "#140350 HAWKINSINURIA". OMIM. Retrieved 14 February 2020.