2.A.106.2.2
Ca²⁺/Mn²⁺/Mg²⁺:H⁺ antiporter, TMEM165 (PT27; TPARL; SLC64A1) of 324 aas and 7 TMSs in a 1 (N-terminal) + 3 + 3 TMS arrangement (Demaegd et al. 2013).  It may be both a Ca²⁺:H⁺ and a Mn²⁺:H⁺ antiporter (Dulary et al. 2016; Stribny et al. 2020), catalyzing uptake of Mn²⁺ from the cytoplasm into the golgi lumen.  TMEM165 has been linked to congenital disorders of glycosylation (CDG) (Foulquier et al. 2012). It may influence glycosylation due to its Mn²⁺ transport activity that regulates Mn²⁺ homeostasis in the golgi (Thines et al. 2018). TMEM165 is also required for milk production (Snyder et al. 2019). In humans, both Ca²⁺ and Mn²⁺ are required for proper protein glycosylation in cells (Stribny et al. 2020). TMEM165, a Golgi transmembrane protein, is a novel marker for hepatocellular carcinoma, and its depletion impairs invasion activity (Lee et al. 2018). The pathogenicity of TMEM165 variants using structural modeling based on AlphaFold 2 predictions has been presented (Legrand et al. 2023). Mutations in the gene encoding TMEM165 are a cause of a new type of congenital disorder of glycosylation (CDG) (Jankauskas et al. 2024). Comprehensive studies of TMEM165 in different model systems, including mammals, yeast, and fish uncovered the new realm of Mn²⁺ homeostasis regulation. TMEM165 was shown to act as a Ca²⁺/Mn²⁺:H⁺ antiporter in the medial- and trans-Golgi network, pumping the metal ions into the Golgi lumen and protons outside. Disruption of TMEM165 antiporter activity results in defects in N- and O-glycosylation of proteins and glycosylation of lipids. Impaired glycosylation of TMEM165-CDG arises from a lack of Mn²⁺ within the Golgi. Nevertheless, Mn²⁺ insufficiency in the Golgi is compensated by the activity of the ATPase SERCA2. TMEM165 turnover has also been found to be regulated by the Mn²⁺ cytosolic concentration. Besides causing CDG, the functional involvement of TMEM165 in several other pathologies including cancer and mental health disorders has been described. This systematic review summarizes the available information on TMEM165 molecular structure, cellular function, and its roles in health and disease (Jankauskas et al. 2024).  It may catalyze Ca²⁺ import into lysosomes (Zhang et al. 2025).