Guanosine triphosphate (GTP) cyclohydrolase I, the rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin (BH4), is subject to feedback inhibition by BH4, a cofactor for phenylalanine hydroxylase. Inhibition was found to depend specifically on BH4 and the presence of another protein (p35). The inhibition occurred through BH4-dependent complex formation between p35 protein and GTP cyclohydrolase I. Furthermore, the inhibition was specifically reversed by phenylalanine, and, in conjunction with p35, phenylalanine reduced the cooperativity of GTP cyclohydrolase I. These findings also provide a molecular basis for high plasma BH4 concentrations observed in patients with hyperphenylalaninemia caused by phenylalanine hydroxylase deficiency.

https://science.sciencemag.org/content/sci/260/5113/1507.full.pdf

Feedback regulation mechanisms for the control of GTP cyclohydrolase I activity

Evolution of Neurotransmitter Receptor Systems

Queuine, a modified base found in transfer RNA, appears to be a new dietary factor because (i) previous studies have shown that mice require it for the expression of queuine-containing transfer RNA's but apparently do not synthesize it, and (ii) significant amounts of free queuine are present in common plant and animal food products.

Queuine, a modified base incorporated posttranscriptionally into eukaryotic transfer RNA: wide distribution in nature

Guanosine triphosphate cyclohydrolase, the enzyme that is apparently rate-limiting in biopterin biosynthesis, is increased in adrenal cortex and medulla of rats treated with insulin or reserpine. Denervation and hypophysectomy block the increase in medullary and cortical enzyme activity, respectively, whereas cycloheximide presents the increase in both tissues. These results provide evidence for induction and regulation of guanosine triphosphate cyclohydrolase.

Biopterin cofactor biosynthesis: independent regulation of GTP cyclohydrolase in adrenal medulla and cortex

Long-term cold exposure (5–7 days) is known to induce concomitant increases in the levels of adrenomedullary tyrosine hydroxylase (TH) RNA, protein, and enzyme activity. In this report, we compare the time courses of these changes and investigate the effects of cold exposure on the levels of biopterin, the cofactor required for tyrosine hydroxylation. After only 1 h of cold exposure, TH mRNA abundance increased 71% compared with nonstressed controls. Increases in total cellular TH RNA levels were maximal (threefold over control values) within 3–6 h of cold exposure and remained elevated throughout the duration of the experiment (72 h). TH protein levels increased rapidly after 24 h of cold exposure and reached a maximal value threefold above that of controls at 48–72 h. Despite the relatively rapid and large elevations in TH RNA and protein content, only modest increases in TH activity were detected during the initial 48 h of cold exposure. Adrenomedullary biopterin increased rapidly after the onset of cold exposure, rising to a level approximately twofold that of the nonstressed controls at 24 h, and remained at this level throughout the duration of the stress period. Taken together, the results of this time course study indicate that cold-induced alterations in adrenal TH activity are mediated by multiple cellular control mechanisms, which may include pre- and posttranslational regulation. Our findings also suggest that cold stress-induced increases in the levels of the TH cofactor may represent another key event in the sympathoadrenal system's response to cold stress.

Effects of Cold Exposure on Rat Adrenal Tyrosine Hydroxylase: An Analysis of RNA, Protein, Enzyme Activity, and Cofactor Levels

Tetrahydrobiopterin, the cofactor for tyrosine hydroxylase and other monooxygenases, is present in tissues at apparent concentrations much less than those necessary to saturate the corresponding enzymes. Reserpine treatment or insulin-induced hypoglycemia in rats produces a statistically significant increase in the tetrahydrobiopterin content of both the adrenal medulla and the cortex. Adrenal denervation and hypophysectomy selectively block the increases in cofactor level in medulla and cortex, respectively, while cycloheximide prevents the increase in both tissues. Reserpine did not increase cofactor levels in liver, kidney, or corpus striatum but decreased that of the pineal gland. These results suggest that tetrahydrobiopterin is under neural control in the medulla and hormonal control in the cortex and that increases in cofactor may result from induction of enzyme(s) in the biosynthetic pathway. These results demonstrate regulation of tissue tetrahydrobiopterin and are consistent with the suggestion that cofactor levels participate in the regulation of tyrosine hydroxylase in the adrenal medulla and may have a function, as yet undetermined, in the adrenal cortex.

O H Viveros

Papers

Tetrahydrobiopterin increases in adrenal medulla and cortex: a factor in the regulation of tyrosine hydroxylase.