4Z3K

Human sepiapterin reductase in complex with the cofactor NADP+ and the trypthophan metabolite xanthurenic acid

Summary for 4Z3K

• Entry DOI: 10.2210/pdb4z3k/pdb
• Related: 4XWY
• Descriptor: Sepiapterin reductase, NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, Xanthuric acid, ... (6 entities in total)
• Functional Keywords: sepiapterin-reductase, xanthurenic acid, inhibitor, tryptophan-metabolite, oxidoreductase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P35270
• Total number of polymer chains: 4
• Total formula weight: 123998.39

Authors

Johnsson, K. (deposition date: 2015-03-31, release date: 2015-11-18, Last modification date: 2024-01-10)

Primary citation

Haruki, H.,Hovius, R.,Pedersen, M.G.,Johnsson, K.
Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid.
J.Biol.Chem., 291:652-657, 2016

PubMed Abstract: Tryptophan metabolites in the kynurenine pathway are up-regulated by pro-inflammatory cytokines or glucocorticoids, and are linked to anti-inflammatory and immunosuppressive activities. In addition, they are up-regulated in pathologies such as cancer, autoimmune diseases, and psychiatric disorders. The molecular mechanisms of how kynurenine pathway metabolites cause these effects are incompletely understood. On the other hand, pro-inflammatory cytokines also up-regulate the amounts of tetrahydrobiopterin (BH4), an enzyme cofactor essential for the synthesis of several neurotransmitter and nitric oxide species. Here we show that xanthurenic acid is a potent inhibitor of sepiapterin reductase (SPR), the final enzyme in de novo BH4 synthesis. The crystal structure of xanthurenic acid bound to the active site of SPR reveals why among all kynurenine pathway metabolites xanthurenic acid is the most potent SPR inhibitor. Our findings suggest that increased xanthurenic acid levels resulting from up-regulation of the kynurenine pathway could attenuate BH4 biosynthesis and BH4-dependent enzymatic reactions, linking two major metabolic pathways known to be highly up-regulated in inflammation.

PubMed: 26565027
DOI: 10.1074/jbc.C115.680488

Experimental method

X-RAY DIFFRACTION (2.35 Å)