BH4

A neopterin level above 2.0 nmol/L signals that immune activation is consuming BH4 at the expense of NO and neurotransmitter production. BH4 is recycled from its oxidized form BH2 by DHFR; methotrexate is a known inhibitor of this enzyme and can impair the recycling loop. BH4 is a rate-limiting cofactor for all three NOS isoforms and is also required for serotonin and dopamine synthesis from phenylalanine. As homocysteine rises, BH4 bioavailability falls, simultaneously impairing both NO production and neurotransmitter synthesis. When stimulated by LPS or IFN-γ, GTPCH1 preferentially produces neopterin instead of BH4, diverting the pathway away from NO production.