FIGURE 7.

DHFR activity in liver is not affected by TGT status suggesting an increase in BH2 production accounts for the elevated levels seen in plasma and urine. a, activity of DHFR in liver was determined spectrophotometrically using 7,8-dihydrofolate as substrate. (n = 3 measurements from three individual animals per group.) b, model showing possible reasons for BH2 accumulation in TGT-deficient animals. Under conditions of full queuosine modification of (t)RNA, only basal levels of BH2 are produced and are cleared by DHFR. However, when (t)RNA is unmodified by queuosine, BH2 production is enhanced, despite normal DHFR activity, either through (i) increased production of BH2 by sepiapterin reductase (SR)/carbonyl reductase (CR) at the pyruvoyl tetrahydrobiopterin to BH4 reaction step, (ii) increased production and tautomerization of quinonoid dihydrobiopterin caused by a defect at the DHPR recycling step, (iii) nonenzymatic oxidation of BH4, or (iv) competition between BH2 and dihydrofolate for reduction by the DHFR enzyme.