Role of excessive ubiquitination in BH4 deficiency
The rate-limiting enzyme GTPCH1 (GTP cyclohydrolase 1) in the de novo synthesis of tetrahydrobiopterin (BH4) was shown to interact with polyubiquitin in a non-covalent matter (R1)
GTPCH1 protein degradation has been reported in animal models of several diseases, including diabetes mellitus and hypertension. Taken together, we conclude that GTPCH1 non-covalently interacts with polyubiquitin via an ubiquitin-binding domain. The polyubiquitin binding directs GTPCH1 ubiquitination and proteasome degradation. (R1)
Another study showed that Increased (abnormal) ubiquitination of proteins can happen in constitutive autophagy deficiency, or when lysosomal degradation is impaired (p62 is a protein that targets other proteins for selective autophagy):
These results indicate that p62 turnover is mediated by autophagy. Autophagic breakdown of p62 appears to occur irrespective of cell type. … Similarly, lysosomal inhibition resulted in marked accumulation of p62.
When lysosomal inhibitors were added to cultured hepatocytes, the majority of p62 accumulated around the perinuclear region, where it colocalized with the lysosomal marker LysoTracker, suggesting the turnover of p62 together with LC3II in lysosomes. (R2)
Note
This suggest that impaired autophagy or impaired lysosomal degradation can lead to accumulation of p62, which will reduce amount of other proteins by excessive targeting for degradation.
This effect was shown for KEAP1 protein:
Autophagy deficiency in the liver because of liver-specific disruption of the Atg7 gene in mice is found to give rise to aberrant accumulation of p62 and subsequent liver damage. We also found that p62 directly associates with Keap1 and disrupts the interaction between Keap1 and Nrf2, leading to the stabilization of Nrf2 (R3)
Conclusion
Tip
Altogether, impaired autophagy or dysfunctional lysosomes may lead to BH4 deficiency, caused by increased degradation of GTPCH1 protein due to accumulation of p62 protein.