Role of the MetR regulatory system in vitamin B12-mediated repression of the Salmonella typhimurium metE gene.

ABSTRACT Salmonella typhimurium has three distinct transport systems for Mg2+: CorA, MgtA, and MgtB. ThemgtCB operon encodes two proteins, MgtC, a hydrophobic protein with a predicted molecular mass of 22.5 kDa, and MgtB, a 102-kDa P-type ATPase Mg2+ transport protein. ThemgtCB locus has been identified as part of a newSalmonella pathogenicity island, SPI-3. Transcription ofmgtCB is regulated by extracellular Mg2+ via the two-component PhoPQ regulatory system important for virulence. To elucidate MgtC’s role in a low-Mg2+ environment, we looked at growth and transport in strains lacking the CorA and MgtA Mg2+ transporters but expressing MgtB, MgtC, or both.mgtC mgtB+ and mgtC+mgtB+ strains exhibited growth in N minimal medium without added Mg2+ with a 1- to 2-h lag phase. AnmgtC+ mgtB strain was also able to grow in N minimal medium without added Mg2+ but only after a 24-h lag phase. In N minimal medium containing 10 mM Mg2+, all strains grew after a short lag phase; the mgtC+mgtB strain grew to a higher optical density at 600 nm than anmgtC+ mgtB+ strain and was comparable to wild type. The lengthy lag phase before growth in anmgtC+ mgtB strain was not due to lack of expression of MgtC. Western blot analysis indicated that substantial MgtC protein is present by 2 h after suspension in N minimal medium. Surprisingly, in an mgtC+mgtB+ strain, MgtC was undetectable during Mg2+ starvation, although large amounts of MgtB were observed. The lack of expression of MgtC is not dependent on functional MgtB, since a strain carrying a nonfunctional MgtB with a mutation (D379A) also did not make MgtC. Since, during invasion of eukaryotic cells, S. typhimurium appears to be exposed to a low-pH as well as a low-Mg2+ environment, the growth of anmgtC+ mgtB strain was tested at low pH with and without added Mg2+. While significant quantities of MgtC could be detected after suspension at pH 5.2, themgtC+ mgtB strain was unable to grow at pH 5.2 whether or not Mg2+ was present. Finally, using63Ni2+ and 57Co2+ as alternative substrates for the unavailable28Mg2+, cation uptake could not be detected in an mgtC+ mgtB strain after Mg2+starvation. We conclude that MgtC is not a Mg2+ transporter and that it does not have a primary role in the survival of S. typhimurium at low pH.

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THYROID STIMULATORS AND THYROID STIMULATION

Acta Endocrinologica ◽

10.1530/acta.0.0660558 ◽

1971 ◽

Vol 66 (3) ◽

pp. 558-576 ◽

Cited By ~ 15

Author(s):

Gerald Burke

Keyword(s):

Regulatory System ◽

Control Site ◽

Thyroid Cell ◽

Primary Control ◽

Physico Chemical ◽

Site Of Action ◽

Long Acting

ABSTRACT A long-acting thyroid stimulator (LATS), distinct from pituitary thyrotrophin (TSH), is found in the serum of some patients with Graves' disease. Despite the marked physico-chemical and immunologic differences between the two stimulators, both in vivo and in vitro studies indicate that LATS and TSH act on the same thyroidal site(s) and that such stimulation does not require penetration of the thyroid cell. Although resorption of colloid and secretion of thyroid hormone are early responses to both TSH and LATS, available evidence reveals no basic metabolic pathway which must be activated by these hormones in order for iodination reactions to occur. Cyclic 3′, 5′-AMP appears to mediate TSH and LATS effects on iodination reactions but the role of this compound in activating thyroidal intermediary metabolism is less clear. Based on the evidence reviewed herein, it is suggested that the primary site of action of thyroid stimulators is at the cell membrane and that beyond the(se) primary control site(s), there exists a multifaceted regulatory system for thyroid hormonogenesis and cell growth.

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Faculty Opinions recommendation of Role of the LytSR two-component regulatory system in adaptation to cationic antimicrobial peptides in Staphylococcus aureus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718023499.793479411 ◽

2013 ◽

Author(s):

Suzanne Walker ◽

Mithila Rajagopal

Keyword(s):

Staphylococcus Aureus ◽

Antimicrobial Peptides ◽

Regulatory System ◽

Cationic Antimicrobial Peptides ◽

Two Component

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Cubilin, the Intrinsic Factor-Vitamin B12 Receptor in Development and Disease

Current Medicinal Chemistry ◽

10.2174/0929867325666181008143945 ◽

2020 ◽

Vol 27 (19) ◽

pp. 3123-3150 ◽

Cited By ~ 2

Author(s):

Renata Kozyraki ◽

Olivier Cases

Keyword(s):

Vitamin B12 ◽

Cancer Progression ◽

Intrinsic Factor ◽

Basic Research ◽

Toxic Substances ◽

Human Pathology ◽

Peripheral Membrane Protein ◽

Epidermal Growth ◽

Fgf8 Signaling

Gp280/Intrinsic factor-vitamin B12 receptor/Cubilin (CUBN) is a large endocytic receptor serving multiple functions in vitamin B12 homeostasis, renal reabsorption of protein or toxic substances including albumin, vitamin D-binding protein or cadmium. Cubilin is a peripheral membrane protein consisting of 8 Epidermal Growth Factor (EGF)-like repeats and 27 CUB (defined as Complement C1r/C1s, Uegf, BMP1) domains. This structurally unique protein interacts with at least two molecular partners, Amnionless (AMN) and Lrp2/Megalin. AMN is involved in appropriate plasma membrane transport of Cubilin whereas Lrp2 is essential for efficient internalization of Cubilin and its ligands. Observations gleaned from animal models with Cubn deficiency or human diseases demonstrate the importance of this protein. In this review addressed to basic research and medical scientists, we summarize currently available data on Cubilin and its implication in renal and intestinal biology. We also discuss the role of Cubilin as a modulator of Fgf8 signaling during embryonic development and propose that the Cubilin-Fgf8 interaction may be relevant in human pathology, including in cancer progression, heart or neural tube defects. We finally provide experimental elements suggesting that some aspects of Cubilin physiology might be relevant in drug design.

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Current Nanocarrier Strategies Improve Vitamin B12 Pharmacokinetics, Ameliorate Patients’ Lives, and Reduce Costs

Nanomaterials ◽

10.3390/nano11030743 ◽

2021 ◽

Vol 11 (3) ◽

pp. 743

Author(s):

Marco Fidaleo ◽

Stefano Tacconi ◽

Carolina Sbarigia ◽

Daniele Passeri ◽

Marco Rossi ◽

...

Keyword(s):

Side Effects ◽

Vitamin B12 ◽

Memory Performance ◽

Oral Route ◽

High Dose ◽

Human Beings ◽

Inborn Errors ◽

Essential Nutrient

Vitamin B12 (VitB12) is a naturally occurring compound produced by microorganisms and an essential nutrient for humans. Several papers highlight the role of VitB12 deficiency in bone and heart health, depression, memory performance, fertility, embryo development, and cancer, while VitB12 treatment is crucial for survival in inborn errors of VitB12 metabolism. VitB12 is administrated through intramuscular injection, thus impacting the patients’ lifestyle, although it is known that oral administration may meet the specific requirement even in the case of malabsorption. Furthermore, the high-dose injection of VitB12 does not ensure a constant dosage, while the oral route allows only 1.2% of the vitamin to be absorbed in human beings. Nanocarriers are promising nanotechnology that can enable therapies to be improved, reducing side effects. Today, nanocarrier strategies applied at VitB12 delivery are at the initial phase and aim to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients’ lives. The safety of nanotechnologies is still under investigation and few treatments involving nanocarriers have been approved, so far. Here, we highlight the role of VitB12 in human metabolism and diseases, and the issues linked to its molecule properties, and discuss how nanocarriers can improve the therapy and supplementation of the vitamin and reduce possible side effects and limits.

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