Structural insight into the aromatic amino acid hydroxylases
and their disease-related mutant forms.
The metabolism of PB is inhibited, whereas that of PM is variably affected - hydroxylases
are up-regulated and demethylases are down-regulated.
The oxygen sensor enzymes, HIF-prolyl hydroxylases
(PHD1-3) prevent HIF activity under normoxic conditions.
The hydroxylation of proline and lysine residues by the collagen hydroxylases
is coupled with a stoichiometric decarboxylation of 2-oxoglutarate.
Inside the renal tubular cells, DBP is degraded and 25 (OH) D is released for metabolism by 1 [alpha] or 24 hydroxylases
and the protein disulfide isomerase subunit of prolyl 4hydroxylases
Both enzymes are pteridin-dependent aromatic amino acid hydroxylases
and are highly homologous, reflecting a common evolutionary origin from a single genetic locus (Cooper et al.
When screening for other genetic traits containing homologous genes such as CYP11B1 and CYP11B2 hydroxylases
, mixed primer amplification combined with size differentiation would help ensure that both chromosomes amplify.
FibroGen has applied its expertise in the field of tissue fibrosis - with matricellular proteins, such as connective tissue growth factor (CTGF), and with matrix assembly enzymes, such as prolyl hydroxylases
- to the clinical development of anti-CTGF agents and prolyl hydroxylase
inhibitors in therapies meeting serious unmet medical needs.
Nickel depletes intracellular ascorbate, which leads to the inhibition of cellular hydroxylases
, manifested by the loss of hypoxia-inducible factor (HIF)-1[alpha] and -2[alpha] hydroxylation and hypoxia-like stress.
This part of the protein and the cysteine residue therefore seem pivotal for enzymatic function of aromatic amino acid hydroxylases
Using its expertise in the field of tissue fibrosis, in particular with matricellular proteins, such as connective tissue growth factor (CTGF), and matrix assembly enzymes, such as prolyl hydroxylases
, FibroGen is now engaged in clinical development of anti-CTGF therapy and prolyl hydroxylase
inhibitors for serious unmet medical needs.