Pathways

Tyrosine kinase inhibitors (TKIs) block chemical messengers (enzymes) called tyrosine kinases. Tyrosine kinases help to send growth signals in cells, so blocking them stops the cell growing and dividing. Cancer growth blockers can block one type of tyrosine kinase or more than one type. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Tyrosine kinase enzymes (TKs) can be categorized into receptor tyrosine kinases (RTKs), non-receptor tyrosine kinases (NRTKs), and a small group of dual-specificity kinases (DSK) which can phosphorylate serine, threonine, and tyrosine residues. RTKs are transmembrane receptor that includes vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), insulin receptor (InsR) family, and the ErbB receptor family, which includes epidermal growth factor receptors (EGFR) and the human epidermal growth factor receptor-2 (HER2). NRTKs are cytoplasmic proteins that consist of nine families, including Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, and Tec, with the addition of Brl/Sik, Rak/Frk, Rlk/Txk, and Srm, which fall outside the nine defined families. The most notable example of DSKs is the mitogen-activated protein kinase kinases (MEKs), which are principally involved in the MAP pathways. Kinase inhibitors are either irreversible or reversible. The irreversible kinase inhibitors tend to covalently bind and block the ATP site resulting in irreversible inhibition. The reversible kinase inhibitors can further subdivide into four major subtypes based on the confirmation of the binding pocket as well as the DFG motif. Different binding modes of TKIs include Type I inhibitors: competitively bind to the ATP-binding site of active TKs. The arrangement of the DFG motif in type I inhibitors has the aspartate residue facing the catalytic site of the kinase. Type II inhibitors: bind to inactive kinases, usually at the ATP-binding site. The DFG motif in type II inhibitors protrudes outward away from the ATP-binding site. Due to the outward rotation of the DFG motif, many type II inhibitors can also exploit regions adjacent to the ATP-binding site that would otherwise be inaccessible. Type III inhibitors: do not interact with the ATP-binding pocket. Type III inhibitors exclusively bind to allosteric pockets adjacent to the ATP-binding region. Type IV inhibitors: bind allosteric sites far removed from the ATP-binding pocket. Type V inhibitors: refer to a proposed subset of kinase inhibitors that exhibit multiple binding modes

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia II also known as Richner-Hanhart syndrome is an autosomal recessive disorder caused by a mutation in the TAT gene the encodes for tyrosine aminotransferase. A defect in this enzyme causes excess tyrosine to accumulate in the blood and urine, tyrosine crystals to form in the cornea, and increased excretion in the urine of 4-hydroxyphenylpyruvic acid, hydroxyphenyllactic acid, and p-hydroxyphenylacetic acid. Symptoms commonly appear in early childhood and include: mental retardation, photophobia (increased sensitivity to light), excessive tearing, eye redness and pain and skin lesions of the palms and soles. The patient is treated with restriction of dietary phenylalanine and tyrosine. Sometimes a tyrosine degradation inhibitor is also used to prevents the formation of fumarylacetoacetate from tyrosine. Trosinemia II is commonly misdiagnosed as herpes simplex keratitis.

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).

Tyrosinemia type 3, one of the three types of tyrosinemia, is a rare disorder with only a few reported cases. Tyrosinemia type 3 results from a defect in the HPD gene which codes for 4-hydroxyphenylpyruvate dioxygenase. 4-Hydroxyphenylpyruvate dioxygenase plays a role in the catabolism of tyrosine by catalyzing the conversion of 4-hydroxyphenylpyruvate to homogentisate. A defect in this enzyme causes tyrosine and phenylalanine to accumulate in the blood resulting in increased excretion of tyrosine in the urine. Tyrosinemia type 3 symptoms include: seizures, mental retardation and intermittent ataxia (occasional loss of balance and coordination).

Tyrosinemia type I, also known as fumarylacetoacetase or FAH deficiency, is the most severe type of tyrosinemia, a buildup of tyrosine in the body. It is caused by an autosomal recessive mutation in the the FAH gene that encodes for fumarylacetoacetase, an enzyme that is responsible for the last of five steps that are involved in the metabolic breakdown of tyrosine in the liver and kidneys. The lack of this enzyme's function leads to a buildup of 4-fumarylacetoacetic acid as it couldn't be broken down to fumaric acid and acetoacetic acid. This also leads to an increased concentration of maleylacetoacetic acid. This eventually leads to the increased concentration of L-tyrosine in the body. Symptoms of tyrosinemia type I include jaundice and an enlarged liver, kidney dysfunction, as well as a failure to grow, as foods with high protein and amino acids lead to increased symptoms. Additionally, individuals are more at risk for future liver cancer.