Hexose-6-phosphate dehydrogenase (H6PD) (H6PD)

Hexose-6-phosphate dehydrogenase (H6PD) is an enzyme localized within the lumen of the endoplasmic reticulum (ER) that plays a pivotal role in cellular metabolism and steroid signaling [UniProt, O95479; PubMed, PMID: 15107844]. Unlike its cytosolic counterpart, glucose-6-phosphate dehydrogenase, H6PD utilizes a variety of hexose-6-phosphates to generate NADPH specifically within the ER environment [UniProt, O95479; NCBI Gene, ID: 9563]. This NADPH production is essential for the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme that converts inactive cortisone into active cortisol [PubMed, PMID: 15107844; PubMed, PMID: 15657375]. Consequently, H6PD acts as a key regulator of local glucocorticoid availability, influencing metabolic processes in tissues such as the liver, adipose, and skeletal muscle [PubMed, PMID: 15107844; NCBI Gene, ID: 9563]. Mutations in the H6PD gene are associated with cortisone reductase deficiency, which can lead to hyperandrogenism and polycystic ovary syndrome (PCOS) [PubMed, PMID: 15657375]. Due to its role in cortisol activation, H6PD is considered a potential therapeutic target for treating metabolic syndrome, obesity, and type 2 diabetes [PubMed, PMID: 15107844; NCBI Gene, ID: 9563]. While specific clinical inhibitors are not yet widely available, research focuses on modulating H6PD activity to improve insulin sensitivity and reduce the complications of glucocorticoid excess [UniProt, O95479; NCBI Gene, ID: 9563].

Other names

Glucose 1-dehydrogenase [UniProt, O95479]GDH [UniProt, O95479]H6PDH [UniProt, O95479]Endoplasmic reticulum glucose-6-phosphate dehydrogenase [NCBI Gene, ID: 9563]

Inhibition of H6PD reduces the supply of NADPH to 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), thereby preventing the conversion of inactive cortisone to active cortisol [PubMed, PMID: 15107844; NCBI Gene, ID: 9563].