Pathways

A transient defect in tyrosine metabolism is a common aminoacidopathy in the premature and full-term human infant. This disorder, termed neonatal tyrosinemia, was first described by Levine and Gordon in 1939. In the intervening years other workers have studied this disorder, and have noted the concurrence of tyrosinemia and tyrosyluria. In a current survey of 15,000 infants, 6 mild tyrosinemia occurred during the first week of life in 10% of full-term infants, and severe tyrosinemia occurred in approximately 30% of premature infants. The enzymatic basis of neonatal tyrosinemia is complex and involves the susceptibility of p-hydroxyphenylpyruvic acid oxidase to inhibition in the presence of its substrate, p-hydroxyphenylpyruvic acid and derivatives. The inhibition is reversible by removal of excess substrate and by reducing agents such as ascorbic acid, 2, 6-dichiorophenolindophenol, and a number of hydroquinone and phenylenediamine compounds.

A transient defect in tyrosine metabolism is a common aminoacidopathy in the premature and full-term human infant. This disorder, termed neonatal tyrosinemia, was first described by Levine and Gordon in 1939. In the intervening years other workers have studied this disorder, and have noted the concurrence of tyrosinemia and tyrosyluria. In a current survey of 15,000 infants, 6 mild tyrosinemia occurred during the first week of life in 10% of full-term infants, and severe tyrosinemia occurred in approximately 30% of premature infants. The enzymatic basis of neonatal tyrosinemia is complex and involves the susceptibility of p-hydroxyphenylpyruvic acid oxidase to inhibition in the presence of its substrate, p-hydroxyphenylpyruvic acid and derivatives. The inhibition is reversible by removal of excess substrate and by reducing agents such as ascorbic acid, 2, 6-dichiorophenolindophenol, and a number of hydroquinone and phenylenediamine compounds.

Gadoversetamide is a drug that is not metabolized by the human body as determined by current research and biotransformer analysis. Gadoversetamide passes through the liver and is then excreted from the body mainly through the kidney.

Ubiquinone is also known as coenzyme Q10. It is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the isoprenyl chemical subunits. Ubiquinone is a carrier of hydrogen atoms (protons plus electrons) and functions as an ubiquitous coenzyme in redox reactions, where it is first reduced to the enzyme-bound intermediate radical semiquinone and in a second reduction to ubiquinol (Dihydroquinone; CoQH2). Ubiquinone is not tightly bound or covalently linked to any known protein complex but is very mobile. In eukaryotes ubiquinones were found in the inner mito-chondrial membrane and in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes and peroxisomes. The benzoquinone portion of Coenzyme Q10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is also used for the first steps of cholesterol biosynthesis. The enzyme para-hydroxybenzoate polyprenyltransferase catalyzes the condensation of p-hydroxybenzoate with polyprenyl diphosphate to generate ubiquinone.

Ubiquinone’s distinctive structure is defined by a polyisoprenoid side chain connected to a benzoquinone ring. It serves multiple roles in plants, functioning as an electron transporter in inner mitochondrial membranes, as well as acting as an antioxidant to protect against free radicals. The biosynthesis of ubiquinone is connected to the biosynthesis of tyrosine, tryptophan, and phenylalanine through the shared compounds L-tyrosine and chorismate. Its biosynthesis also takes place in many organelles, with key steps occurring in the mitochondria, chloroplasts, and peroxisomes of plant cells. The compound L-tyrosine begins in the cytoplasm and is converted to homogentisic acid before it can enter the chloroplast through the transporter homogentisate prenyltransferase. Once in the chloroplast, homogentisic acid can follow one of three different sets of reactions, ultimately forming five different compounds, plastoquinol-9, α-tocopherol, β-tocopherol, α-tocotrienol and β-tocotrienol. Pyrophosphate compounds from reactions early in all three sets are provided as products from terpenoid backbone biosynthesis. Meanwhile, chorismate, which also begins in the cytoplasm, can follow two distinct pathways. The first involves its transfer into the mitochondrion, where it undergoes a series of reactions until it forms ubiquinone. This ubiquinone can be used for oxidative phosphorylation within the mitochondrion. The second pathway chorismate follows brings it into the chloroplast, where multiple PHYLLO enzymes catalyze a series of reactions to form 2-succinyl benzoate. With the addition of coenzyme A, 2-succinyl benzoyl-CoA can be moved out of the chloroplast and into the peroxisome. Through a pair of reactions, this compound is ultimately hydrolyzed to form 1,4-dihydroxy-2-naphthoate, which is transported back into the chloroplast to form phylloquinol. Phylloquinone can also react with a hydrogen ion to form phylloquinol in the cell membrane.

Ubiquinone is also known as coenzyme Q10. It is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the isoprenyl chemical subunits. Ubiquinone is a carrier of hydrogen atoms (protons plus electrons) and functions as an ubiquitous coenzyme in redox reactions, where it is first reduced to the enzyme-bound intermediate radical semiquinone and in a second reduction to ubiquinol (Dihydroquinone; CoQH2). Ubiquinone is not tightly bound or covalently linked to any known protein complex but is very mobile. In eukaryotes ubiquinones were found in the inner mito-chondrial membrane and in other membranes such as the endoplasmic reticulum, Golgi vesicles, lysosomes and peroxisomes. The benzoquinone portion of Coenzyme Q10 is synthesized from tyrosine, whereas the isoprene sidechain is synthesized from acetyl-CoA through the mevalonate pathway. The mevalonate pathway is also used for the first steps of cholesterol biosynthesis. The enzyme para-hydroxybenzoate polyprenyltransferase catalyzes the condensation of p-hydroxybenzoate with polyprenyl diphosphate to generate ubiquinone.