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Characterization of a single b-type heme, FAD, and metal binding sites in the transmembrane domain of six-transmembrane epithelial antigen of the prostate (STEAP) family proteins.

ABSTRACT: Six-transmembrane epithelial antigen of the prostate 3 (Steap3) is the major ferric reductase in developing erythrocytes. Steap family proteins are defined by a shared transmembrane domain that in Steap3 has been shown to function as a transmembrane electron shuttle, moving cytoplasmic electrons derived from NADPH across the lipid bilayer to the extracellular face where they are used to reduce Fe(3+) to Fe(2+) and potentially Cu(2+) to Cu(1+). Although the cytoplasmic N-terminal oxidoreductase domain of Steap3 and Steap4 are relatively well characterized, little work has been done to characterize the transmembrane domain of any member of the Steap family. Here we identify high affinity FAD and iron biding sites and characterize a single b-type heme binding site in the Steap3 transmembrane domain. Furthermore, we show that Steap3 is functional as a homodimer and that it utilizes an intrasubunit electron transfer pathway through the single heme moiety rather than an intersubunit electron pathway through a potential domain-swapped dimer. Importantly, the sequence motifs in the transmembrane domain that are associated with the FAD and metal binding sites are not only present in Steap2 and Steap4 but also in Steap1, which lacks the N-terminal oxidoreductase domain. This strongly suggests that Steap1 harbors latent oxidoreductase activity.

SUBMITTER: Kleven MD

PROVIDER: S-EPMC4566230 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Characterization of a single b-type heme, FAD, and metal binding sites in the transmembrane domain of six-transmembrane epithelial antigen of the prostate (STEAP) family proteins.

Kleven Mark D MD Dlakić Mensur M Lawrence C Martin CM

The Journal of biological chemistry 20150723 37

Six-transmembrane epithelial antigen of the prostate 3 (Steap3) is the major ferric reductase in developing erythrocytes. Steap family proteins are defined by a shared transmembrane domain that in Steap3 has been shown to function as a transmembrane electron shuttle, moving cytoplasmic electrons derived from NADPH across the lipid bilayer to the extracellular face where they are used to reduce Fe(3+) to Fe(2+) and potentially Cu(2+) to Cu(1+). Although the cytoplasmic N-terminal oxidoreductase d ...[more]

PMID: 26205815

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Project description:PURPOSE:Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer. METHODS:Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg). RESULTS:Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing. CONCLUSION:DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.

Dataset Information

Characterization of a single b-type heme, FAD, and metal binding sites in the transmembrane domain of six-transmembrane epithelial antigen of the prostate (STEAP) family proteins.

Publications

Characterization of a single b-type heme, FAD, and metal binding sites in the transmembrane domain of six-transmembrane epithelial antigen of the prostate (STEAP) family proteins.

Similar Datasets

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