Biopterin-dependent aromatic amino acid hydroxylases (AAAH) are a family of aromatic

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 ...

hydroxylase

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s which includes phenylalanine 4-hydroxylase (), tyrosine 3-hydroxylase (), and tryptophan 5-hydroxylase (). These enzymes primarily hydroxylate the amino acids

L-phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...

L-tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) 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 ...

, and L-tryptophan, respectively. The AAAH enzymes are functionally and structurally related

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s which act as rate-limiting

catalyst Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

s for important

metabolic pathways In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...

. Each AAAH enzyme contains

iron Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...

and catalyzes the ring hydroxylation of aromatic amino acids using

tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin ( INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the metabolism of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...

(BH4) as a

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

. The AAAH enzymes are regulated by

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

s in their N-termini.

Role in metabolism

In humans,

phenylalanine hydroxylase Phenylalanine hydroxylase (PAH) () is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a clas ...

deficiency can cause

phenylketonuria Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also r ...

, the most common inborn error of

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. Phenylalanine hydroxylase

catalyze Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...

s the conversion of to .

Tyrosine hydroxylase Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA). It does so using molecular oxygen (O2), as well as iron (Fe2+) and ...

catalyzes the

rate-limiting step In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of the ...

catecholamine A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Cate ...

biosynthesis: the conversion of to . Similarly,

tryptophan hydroxylase Tryptophan hydroxylase (TPH) is an enzyme () involved in the synthesis of the monoamine neurotransmitter serotonin. Tyrosine hydroxylase, phenylalanine hydroxylase, and tryptophan hydroxylase together constitute the family of biopterin-depen ...

catalyzes the rate-limiting step in

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

biosynthesis: the conversion of to .

Structure

It has been suggested that the AAAH enzymes each contain a conserved C-terminal

catalytic Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...

regulatory Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...

(R) domain. It is possible that the R

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

s arose from genes that were recruited from different sources to combine with the common

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

for the catalytic core. Thus, by combining with the same C domain, the proteins acquired the unique regulatory properties of the separate R domains.

References

{{InterPro content, IPR019774 Protein domains