This entry represents the paired amphipathic helix (PAH) repeat. Sin3 proteins have at least three PAH domains (PAH1, PAH2, and PAH3) [, ]. They are components of a co-repressor complex that silences transcription, playing important roles in the transition between proliferation and differentiation. Sin3 proteins are recruited to the DNA by various DNA-binding transcription factors such as the Mad family of repressors, Mnt/Rox, PLZF, MeCP2, p53, REST/NRSF, MNFbeta, Sp1, TGIF and Ume6 []. Sin3 acts as a scaffold protein that in turn recruits histone-binding proteins RbAp46/RbAp48 and histone deacetylases HDAC1/HDAC2, which deacetylate the core histones resulting in a repressed state of the chromatin []. The PAH domains are protein-protein interaction domains through which Sin3 fulfils its role as a scaffold. The PAH2 domain of Sin3 can interact with a wide range of unrelated and structurally diverse transcription factors that bind using different interaction motifs. For example, the Sin3 PAH2 domain can interact with the unrelated Mad and HBP1 factors using alternative interaction motifs that involve binding in opposite helical orientations [].
This entry represents the large, tetrameric form of phenylalanine-4-hydroxylase (PAH; ), as found in metazoans. PAH irreversibly converts phenylalanine to tyrosine, and is known to be the rate-limiting step in phenylalanine catabolism in some systems. It is closely related to metazoan tyrosine 3-monooxygenase and tryptophan 5-monoxygenase, and more distantly to monomeric phenylalanine-4-hydroxylases of some Gram-negative bacteria. The member of this family from Drosophila has been described as having both phenylalanine-4-hydroxylase and tryptophan 5-monoxygenase activity []. However, a Drosophila member of the tryptophan 5-monoxygenase clade has subsequently been discovered.A deficiency in PAH can lead to phenylketonuria (PKU), an autosomal recessive genetic disorder characterised by an inability to metabolise phenylalanine, resulting in elevated Phe levels in the bloodstream that can lead to mental retardation if left untreated [].
Proteins in this entry contain N-terminal PAH (paired amphipathic helix) repeats, a histone deacetylase interacting domain, and a Sin3, C-terminal domain. Sin3 proteins have at least three PAH domains (PAH1, PAH2, and PAH3). They are components of a co-repressor complex that silences transcription, playing important roles in the transition between proliferation and differentiation. Sin3 proteins are recruited to the DNA by various DNA-binding transcription factors such as the Mad family of repressors, Mnt/Rox, PLZF, MeCP2, p53, REST/NRSF, MNFbeta, Sp1, TGIF and Ume6 []. Sin3 acts as a scaffold protein that in turn recruits histone-binding proteins RbAp46/RbAp48 and histone deacetylases HDAC1/HDAC2, which deacetylate the core histones resulting in a repressed state of the chromatin []. The PAH domains are protein-protein interaction domains through which Sin3 fulfils its role as a scaffold. The PAH2 domain of Sin3 can interact with a wide range of unrelated and structurally diverse transcription factors that bind using different interaction motifs. For example, the Sin3 PAH2 domain can interact with the unrelated Mad and HBP1 factors using alternative interaction motifs that involve binding in opposite helical orientations []. The Sin3, C-terminal domain forms interactions with histone deacetylases [].
Lipin family consists of lipin proteins, which are magnesium-dependent phosphatidate phosphatase enzymes that provide diacylglycerol for synthesis of triacylglycerol and phospholipids. Mammalian lipin proteins also exhibit transcriptional coactivator activity []. Common polymorphisms in human LPIN1 and LPIN2 genes are associated with traits underlying common metabolic diseases, including increased adiposity, hypertension, insulin sensitivity, and response to commonly used antidiabetic drugs []. Saccharomyces cerevisiae lipin, PAH1, controls transcription of phospholipid biosynthetic genes and nuclear structure by regulating the amount of membrane present at the nuclear envelope. PAH is also involved in plasmid maintenance, in respiration and in cell proliferation [, , ].
This entry represents the small, monomeric form of phenylalanine-4-hydroxylase (PAH; ), as found in a certain Gram-negative bacteria. The enzyme is biopterin and metal dependent, and acts to irreversibly convert phenylalanine to tyrosine, the rate-limiting step in phenylalanine catabolism in some systems:L-phenylalanine + tetrahydrobiopterin + O2 = L-tyrosine + dihydrobiopterin + H2O The structure of PAH from Colwellia psychrerythraea (strain 34H / ATCC BAA-681), which binds tetrahydrobiopterin (BH4) as cofactor, is a cold-active form of the enzyme that has increased stability and flexibility around the active site [].
Sin3a is a transcriptional repressor and a homologue of the SIN3 repressor from yeast. Sin3a associates with the strong repressive isoform of Mxi1, a helix-loop-helix leucone zipper that associates with Max to antagonize Myc oncogenic activities []. Unlike Mxi1 and Myc, expression of Sin3a does not vary during development []. Sin3a is a component of several complexes, including the REST-CoREST repressor complex [], the PER complex which maintains circadian rhythm []and the Sin3 HDAC complex []. Sin3a also interacts with FOXK1 to regulate cell cycle progression []. Sin3a has three PAH domains by which it interacts with HCFC1, REST and SAP30 [, ].
Hydroxylation of the aromatic amino acids phenylalanine, tyrosine andtryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin(BH4) dependent enzymes: the aromatic amino acid hydroxylase []. Theseenzymes are structurally and functionally similar. The eukaryotic formsinclude a regulatory N-terminal domain, a catalytic domain and a C-terminaloligomerization motif. The eukaryotic enzymes are all homotetramers [, ].Three-dimensional structures have been determined for the three types ofenzymes. The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function [].Enzymes that belong to the aromatic amino acid hydroxylase family are listedbelow:Phenylalanine-4-hydroxylase () (PAH). Catalyzes the conversionof phenylalanine to tyrosine. In humans, deficiencies []of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum [], PAH is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa [].Tyrosine 3-hydroxylase () (TYH). Catalyzes the rate limitingstep in catecholamine biosynthesis: the conversion of tyrosine to 3,4-dihydroxy-L-phenylalanine.Tryptophan 5-hydroxylase () (TRH). Catalyzes the rate-limitingstep in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy-anthranilate.This entry represents a domain containing the catalytic domain and the coiled-coil C-terminal oligomerization motif.
Hydroxylation of the aromatic amino acids phenylalanine, tyrosine andtryptophan is carried out by a family of non-heme iron and tetrahydrobiopterin(BH4) dependent enzymes: the aromatic amino acid hydroxylase []. Theseenzymes are structurally and functionally similar. The eukaryotic formsinclude a regulatory N-terminal domain, a catalytic domain and a C-terminaloligomerization motif. The eukaryotic enzymes are all homotetramers [, ].Three-dimensional structures have been determined for the three types ofenzymes. The iron atom is bound to three amino acid residues, two close histidine and a more distant acidic residue. This arrangement of ligands has been observed in a number of metalloproteins with divergent function [].Enzymes that belong to the aromatic amino acid hydroxylase family are listedbelow:Phenylalanine-4-hydroxylase () (PAH). Catalyzes the conversionof phenylalanine to tyrosine. In humans, deficiencies []of PAH are the cause of phenylketonuria, the most common inborn error of amino acid metabolism. In the bacteria Chromobacterium violaceum [], PAH is copper-dependent; it is iron-dependent in Pseudomonas aeruginosa [].Tyrosine 3-hydroxylase () (TYH). Catalyzes the rate limitingstep in catecholamine biosynthesis: the conversion of tyrosine to 3,4-dihydroxy-L-phenylalanine.Tryptophan 5-hydroxylase () (TRH). Catalyzes the rate-limitingstep in serotonin biosynthesis: the conversion of tryptophan to 3-hydroxy-anthranilate.This entry represents a domain containing the catalytic domain and the coiled-coil C-terminal oligomerization motif.
This entry represents the paired amphipathic helix (PAH) repeat. Sin3 proteins have at least three PAH domains (PAH1, PAH2, and PAH3) [, ]. They are components of a co-repressor complex that silences transcription, playing important roles in the transition between proliferation and differentiation. Sin3 proteins are recruited to the DNA by various DNA-binding transcription factors such as the Mad family of repressors, Mnt/Rox, PLZF, MeCP2, p53, REST/NRSF, MNFbeta, Sp1, TGIF and Ume6 []. Sin3 acts as a scaffold protein that in turn recruits histone-binding proteins RbAp46/RbAp48 and histone deacetylases HDAC1/HDAC2, which deacetylate the core histones resulting in a repressed state of the chromatin []. The PAH domains are protein-protein interaction domains through which Sin3 fulfils its role as a scaffold. The PAH2 domain of Sin3 can interact with a wide range of unrelated and structurally diverse transcription factors that bind using different interaction motifs. For example, the Sin3 PAH2 domain can interact with the unrelated Mad and HBP1 factors using alternative interaction motifs that involve binding in opposite helical orientations [].Structurally, PAH2 is composed of four helices arranged in an open up-and-down bundle fold which binds α-helical peptides.
