Mannose-1-phosphate guanylyltransferase regulatory subunit alpha (GMPPA)

Mannose-1-phosphate guanylyltransferase regulatory subunit alpha (GMPPA) is a regulatory, non-catalytic subunit of the mannose-1-phosphate guanylyltransferase complex, which also includes the catalytic subunit GMPPB. While homologous to the enzyme that catalyzes the conversion of mannose-1-phosphate and GTP into GDP-mannose—a key precursor for N-linked glycosylation—GMPPA itself has no catalytic activity. Instead, GMPPA acts as an allosteric feedback inhibitor of GMPPB, modulating GDP-mannose levels within the cell by responding to product concentrations[2][4]. Deficiency of GMPPA results in a congenital disorder of glycosylation (AAMR syndrome), marked by symptoms such as muscle weakness, hypotonia, cognitive impairment, and alacrima. Studies in knockout mice confirm GMPPA’s role in neuromuscular integrity and its regulatory impact on protein glycosylation. No drugs are currently known to directly target GMPPA, but dietary interventions have shown potential for mitigating metabolic consequences of its deficiency[2][3][4]. Key points: - **Enzyme complex regulatory subunit, not a catalytic enzyme itself**. - **Key regulator of glycosylation precursor levels via feedback inhibition**. - **Pathogenic mutations cause GMPPA-congenital disorder of glycosylation (AAMR syndrome) with neuromuscular and cognitive symptoms**[2][4]. - No direct pharmacological agents known to target GMPPA specifically.

Other names

Mannose-1-phosphate guanylyltransferase regulatory subunit alphaGMPPAGMPP-alphaGDP-mannose pyrophosphorylase AGTP-mannose-1-phosphate guanylyltransferase alphaAAMRepididymis secretory sperm binding protein

Allosteric inhibition of GMPPB (GDP-mannose pyrophosphorylase B) through feedback by GDP-mannose