Searched for: data_source:HUMANCYC [All Organisms, All Data Sources]

Summary:  Mammals |FRAME: 4-hydroxybenzoate 4-hydroxybenzoate| from |FRAME: TYR L-tyrosine|, as described in this pathway. This important pathway has received surprisingly little attention, and has not been characterized very well. A pathway for the conversion of |FRAME: TYR L-tyrosine| to |FRAME: 4-hydroxybenzoate 4-hydroxybenzoate| was proposed already in 1960, based on urinary excretion studies on animals administered with various phenolic acids and the incorporation of radiolabeled phenolic acids into ubiquinone by rat liver and yeast |CITS: [Booth60]|. Based on those results, it was suggested that |FRAME: TYR L-tyrosine| is converted to |FRAME: P-HYDROXY-PHENYLPYRUVATE 4-hydroxyphenylpyruvate|, which is then modified to |FRAME: 4-HYDROXYPHENYLLACTATE 4-hydroxyphenyllactate| and |FRAME: COUMARATE 4-coumarate| |CITS: [Booth60]|. These results were confirmed by additional work performed with rat |CITS: [14081946][14253463][6369767]|. The later part of the pathway, starting with |FRAME: COUMARATE 4-coumarate|, has not been studied much in animals. In plants it has been shown that |FRAME: COUMARATE 4-coumarate| is converted to |FRAME: 4-hydroxybenzoate 4-hydroxybenzoate| either directly (see |FRAME: PWY-6431 4-hydroxybenzoate biosynthesis IV|) or via CoA derivatives such as |FRAME: P-COUMAROYL-COA 4-coumaroyl-CoA| and |FRAME: CPD-201 4-hydroxybenzoyl-CoA| (see |FRAME: PWY-6435 4-hydroxybenzoate biosynthesis V|).

Summary:  In humans, |FRAME: PHE| is an indispensable dietary amino acid, which may either be used for protein synthesis or converted to the amino acid |FRAME: TYR|, the precursor for catecholamine and thyroid hormone synthesis. |FRAME: TYR| is not considered an indispensable component of diet, despite being an essential component of body proteins, because it can be synthesized from |FRAME: PHE| |CITS:[4265522][1093910]|. |FRAME: CPLX-7067| (EC 1.14.16.1) is responsible for the irreversible oxidation of the essential amino acid |FRAME: PHE| to |FRAME: TYR|. The enzyme is found mostly in the liver |CITS: [4004813]| and in the kidney |CITS: [10655515]|, and its subcellular location is the cytoplasm. The enzyme, whose active form is tetrameric, requires the binding of L-phenylalanine to the regulatory domain in order to promote phosphorylation of Ser16, followed by a conformational change, which allows the formation of active tetramers from inactive precursor dimers. Once the active tetrameric form of the enzyme has been produced, |FRAME: PHE| and the cofactor |FRAME: TETRA-H-BIOPTERIN| can bind to the active site domain initiating catalysis. In addition, |FRAME: CPLX-7067| is tightly coupled to |FRAME: CPLX-7068| (EC 4.2.1.96), the key enzyme that is responsible for the recycling of the cofactor |FRAME: TETRA-H-BIOPTERIN|. It has been shown that |FRAME: CPLX-7068| increases the rate of |FRAME: CPLX-7067| 7-fold, and converts the product |FRAME: CPD-5881| to |FRAME: BIOPTERIN| by dehydration, which is further reduced to |FRAME: TETRA-H-BIOPTERIN| in the presence of NADH by |FRAME: CPLX-7069| (EC 1.6.99.7).

Summary:  In humans, |FRAME: CYS| is synthesized from |FRAME: MET|, an essential amino acid that must be provided in food |CITS: [3309559]|. More accurately, the cysteine sulfur is derived from methionine whereas the carbon and nitrogen of cysteine are derived from |FRAME: SER| |CITS: [3309559]|. L-Methionine is converted to |FRAME: HOMO-CYS| by the actions of |FRAME: CPLX-5142| (EC 2.5.1.6), various S-adenosylmethionine methyltransferases, (EC 2.1.1.-) and |FRAME: CPLX-5161| (EC 3.3.1.1). |FRAME: HOMO-CYS| occupies a branch point in methionine metabolism. In human, about half of the homocysteine formed is irreversibily converted by transsulfuration to |FRAME: CYS|, |FRAME: 2-OXOBUTANOATE|, and |FRAME: AMMONIA| as desribed in this pathway, whereas the remainder is remethylated to |FRAME: MET| |CITS: [4593752][1128236]|. |FRAME: CPLX-5162| (EC 4.2.1.22) is a PLP-dependent enzyme that catalyzes the condensation of |FRAME: HOMO-CYS| and |FRAME: SER| to form |FRAME: L-CYSTATHIONINE|. Finally, |FRAME: L-CYSTATHIONINE| is converted to |FRAME: CYS| by |FRAME: CPLX-5163| (EC 4.4.1.1).

Summary:  General Background Sialic acids are a family of polyhydroxylated α-keto acids that contain nine carbon atoms. Most sialic acids are derivatives of |FRAME: N-ACETYLNEURAMINATE|, or |FRAME: CPD-10734| (KDN). |FRAME: N-ACETYLNEURAMINATE| is the most common sialic acid in humans (this pathway). Their core structures can be modified at the hydroxyl groups, lactonized, or hydroxylated at the acetamido group, generating many derivatives. |FRAME: CPD-262| is a derivative of |FRAME: CMP-N-ACETYL-NEURAMINATE| (see pathway |FRAME: PWY-6144|). Reviewed in |CITS: [15888312] [16897172]|. Sialic acids are usually the terminal sugar residue in the glycan chains of human glycoconjugates (mostly glycoproteins and glycolipids, but also proteoglycans and glycosylphosphatidylinositol anchors). They function in mediating cellular recognition and adhesion events for many important processes such as development, the immune and inflammatory responses, and oncogenesis. About This Pathway |FRAME: N-ACETYLNEURAMINATE| biosynthesis begins with the conversion of |FRAME: UDP-N-ACETYL-D-GLUCOSAMINE| to |FRAME: N-ACETYL-D-MANNOSAMINE|. This reaction involves both an inversion of stereochemistry at C-2 of the sugar moiety and hydrolysis of the glycosidic phosphate bond. |FRAME: N-ACETYL-D-MANNOSAMINE| is then phosphorylated to its 6-phosphate derivative. Condensation with |FRAME: PHOSPHO-ENOL-PYRUVATE| then forms |FRAME: N-ACETYL-NEURAMINATE-9P|, a distinctive biosynthetic step. After dephosphorylation to |FRAME: N-ACETYLNEURAMINATE|, |FRAME: CTP| is used to generate the activated form of sialic acid, |FRAME: CMP-N-ACETYL-NEURAMINATE|. This step is in contrast to activation of other monosaccharides, the activated forms of which use |FRAME: URIDINE| or |FRAME: GUANINE| dinucleotides. The |FRAME: CMP|-activated form is the sialic acid donor for glycoconjugates. Reviewed in |CITS: [15888312] [16897172]|. |FRAME: N-ACETYLNEURAMINATE| is biosynthesized in the cytosol. However, its |FRAME: CMP| derivative, |FRAME: CMP-N-ACETYL-NEURAMINATE|, is formed in the nucleus, enters the cytosol and is then transported into the golgi apparatus by a golgi CMP-sialic acid transporter |CITS: [18713811] [16923816] [8755516]|. In the golgi lumen |FRAME: CMP-N-ACETYL-NEURAMINATE| serves as a sialic acid donor for sialyltransferases in the formation of glycoconjugates. For examples of sialyltransferases see EC 2.4.99.1 through EC 2.4.99.11. |FRAME: CMP-N-ACETYL-NEURAMINATE| can also be hydroxylated to |FRAME: CPD-262| by the |FRAME: CPLX-7746| and transferred to glycoconjugates (as shown in the pathway link). Reviewed in |CITS: [15888312] [16897172]| and |CITS: [18568399]|. The first two reactions are catalyzed by a bifunctinal enzyme that catalyzes the rate-limiting steps in sialic acid biosynthesis. The supply of |FRAME: N-ACETYLNEURAMINATE| is regulated through feedback inhibition by |FRAME: CMP-N-ACETYL-NEURAMINATE| |CITS: [9305887]|. Reviewed in |CITS: [15888312] [16897172]| and |CITS: [18568399]|.

Summary:  General Background |FRAME: Chondroitin-sulfates "Chondroitin sulfate| and |FRAME: Dermatan-Sulfate dermatan sulfate| are related sulfated |FRAME: Glycosaminoglycans "glycosaminoglycans"|. |FRAME: Chondroitin-sulfates "Chondroitin sulfate"| is composed of alternating units of sulfated |FRAME:CPD-12557 N-acetyl-β-D-galactosamine| and |FRAME: CPD-12521 β-D-glucuronate| residues, while in |FRAME: Dermatan-Sulfate dermatan sulfate| the |FRAME: CPD-12521 β-D-glucuronate| residues have largely been converted to |FRAME: CPD-12515 α-L-iduronate|. The |FRAME: CPD-12557 N-acetyl-β-D-galactosamine| residues are substituted to varying degrees with sulfate linked to 4- and/or 6-hydroxyl positions, forming |FRAME: CPD-12516 N-acetyl-β-D-galactosamine 4-sulfate|, |FRAME: CPD-12565 β-N-acetyl-D-glucosamine 6-sulfate| or |FRAME: CPD-12526 N-acetyl-D-galactosamine 4,6-bissulfate|, and to a lesser extent the uronic acid residues may be substituted with sulfate at the 2-hydroxyl position forming |FRAME: CPD-12527 2-O-sulfo-β-D-glucuronate| or |FRAME:CPD-12518 2-O-sulfo-α-L-iduronate|. The uronic acid residues may also be substituted with sulfate at the 3-hydroxyl positions, although this substitution is quite rare. The chondroitin/dermatan chains vary in size up to a hundred or more disaccharide repeating units. Both are usually found attached to assorted core proteins as part of a proteoglycan complex. They are major components of connective tissue matrix (such as skin and cartilage), but are also found on cell surface and basement membranes and in intracellular granules of certain cells. Functions in matrix locations are mainly structural, while functions in membranes are mainly as receptors. The chondroitin/dermatan chains are actually synthesized in situ on the protein chain. They are attached to the core protein via a specific tetrasaccharide known as the "glycoaminoglycan-protein linkage region", which is formed by sequential stepwise additions of the sugar residues to specific core proteins. The synthesis of the linkage region is described in |FRAME: PWY-6557 glycoaminoglycan-protein linkage region biosynthesis|. About This Pathway The linkage region may be extended into mutiple kinds of glycosaminoglycans. However, the addition of an |FRAME: CPD-12557 N-acetyl-β-D-galactosamine| residue prevents the formation of |FRAME: HEPARIN heparin| or |FRAME: Heparan-Sulfate heparan sulfate| and commits the molecule to become chondroitin or dermatan. This reaction is catalyzed by the enzyme chondroitin sulfate N-acetylgalactosaminyltransferase. Humans have two isoforms of this enzyme, encoded by the |FRAME: HS07428 CSGALNACT1| and |FRAME:HS10013 CSGALNACT2| genes |CITS: [11788602][12716890][12433924]|. Once the linkage region has been formed and committed, the polymerzation of the chondroitin/dermatan chain proceeds by the alternate addition of |FRAME: CPD-12521 β-D-glucuronate| and |FRAME: CPD-12557 N-acetyl-β-D-galactosamine| from activated precursors to the non-reducing end of the elongating chain. The addition of both residues is catalyzed by the biofunctional chondroitin sulfate synthases. Humans possess three isoforms of this bifunctional enzyme (|FRAME: HS13400 CHSY1|, |FRAME: HS13103 CHPF| and |FRAME: HS11959 CHSY3|), plus an additional enzyme that can catalyze only the addition of |FRAME: CPD-12521 β-D-glucuronate| (|FRAME: HS12080 CHPF2|) |CITS:[11514575][12907687][12145278]|. It has been suggested that chondroitin polymerization is achieved by multiple combinations of the different enzymes and that each combination may play a unique role in the biosynthesis of chondroitin or dermatan sulfate |CITS:[17253960][18316376]|. Further modifications of |FRAME: Chondroitin-sulfates chondroitin sulfate| and |FRAME: Dermatan-Sulfate dermatan sulfate| are described in the pathways |FRAME: PWY-6567 chondroitin sulfate biosynthesis (late stages)| and |FRAME: PWY-6568 dermatan sulfate biosynthesis (late stages)|, respectively.

Summary:  General Background |FRAME: FARNESYL-PP| (farnesyl pyrophosphate, FPP) is a crucial compound involved in the biosynthesis of a variety of terpenoids including sesquiterpenoids and sterols. Moreover, FPP is also used in posttranslational modifications of proteins (farnesylation) which is believed to act as a membrane attachment device. The biosynthesis of FPP is largely thought to occur in the cytosol where sesquiterpenoids and sterols are produced. This cytosolic FPP is synthesized from the condensation of |FRAME: CPD-4211| (dimethylallyl pyrophosphate, DMAPP) and two molecules of |FRAME: DELTA3-ISOPENTENYL-PP| (isopentenyl pyrophosphate, IPP) originating from the |FRAME:PWY-922|. The synthesis of FPP is the result of two head-to-tail condensation reactions: first |FRAME: GERANYL-PP| (geranyl pyrophosphate, GPP) is formed from the condensation of DMAPP and IPP; then another IPP molecule is added to form FPP.

Summary:  General Background |FRAME: TETRA-H-BIOPTERIN| is a cofactor of several enzymes, including the aromatic amino acid hydroxylases |FRAME: CPLX-7488|, |FRAME: CPLX66-161|, and |FRAME: CPLX-7067| (which are essential for the formation of the neurotransmitters |FRAME: DOPAMINE|, |FRAME: NOREPINEPHRINE|, |FRAME: L-EPINEPHRINE| and |FRAME: SEROTONIN| - see |FRAME: PWY66-301|), all three nitric-oxide synthases (NOS) |FRAME: CPLX-6585|, |FRAME: CPLX-6581|, and |FRAME: CPLX-6582| (see |FRAME: PWY-4983|), and the enzyme |FRAME: CPLX-7489|. In addition, |FRAME: TETRA-H-BIOPTERIN| has been proposed to be involved in promotion of neurotransmitter release in the brain |CITS: [1680529]| and regulation of human melanogenesis |CITS: [8128228]|. Deffciency causes severe neurological disorders characterized by hyperphenylalaninaemia and monoamine neurotransmitter deffciency, and is also implicated in Parkinson's disease, Alzheimer's disease and depression (|CITS: [11592814] [10727395]|. |FRAME: TETRA-H-BIOPTERIN| is present in probably every cell or tissue |CITS: [10727395]|. About This Pathway While most of the |FRAME: TETRA-H-BIOPTERIN| in mammalian cells is probably formed as described in the pathway |FRAME: PWY-5663|, a study performed with rat brains has shown that when the activity of the enzyme |FRAME: CPLX-7490| is limiting, a second pathway can lead to |FRAME: TETRA-H-BIOPTERIN| production |CITS: [2656673]|. In this route, |FRAME: 6-PYRUVOYL-5678-TETRAHYDROPTERIN| is converted by the enzyme |FRAME: MONOMER-13405| to |FRAME: 6-LACTOYL-5678-TETRAHYDROPTERIN|, which is then converted to |FRAME: TETRA-H-BIOPTERIN| by |FRAME: CPLX-7490|.