Cobalamin transport

About: Cobalamin transport is a research topic. Over the lifetime, 72 publications have been published within this topic receiving 3088 citations.

Pathophysiology of Lysosomal Transport

Abstract: INTRODUCTION (Jess Thoene). APPROACHES TO THE STUDY OF LYSOSOMAL TRANSPORT (Alice Greene and Jerry Schneider). LYSOSOMAL TRANSPORT OF AMINO ACIDS. Lysosomal Cystine Transport (William Gahl). Lysosomal Transport of Small and Large Neutral Amino Acids (Hans Andersson). Lysosomal Transport Systems for Cationic and Anionic Amino Acids: Systems c and d (Ronald Pisoni). LYSOSOMAL TRANSPORT OF INORGANIC IONS. The Transport of Phosphate and Calcium by Human Fibroblast Lysosomes (Ronald Pisoni and Jess Thoene). Lysosomal Sulfate Transport (Jaydutt Vadgama and Adam Jonas). LYSOSOMAL TRANSPORT OF OTHER METABOLITES. Lysosomal Nucleic Acid Catabolism and Carrier Mediated Transport of Nucleosides (Ronald Pisoni and Jess Thoene). Lysosomal Transport of Sugars: Normal and Pathological (Frank Tietze). Lysosomal Cobalamin Transport (Susan Sillaots and David Rosenblatt). TRANSPORT OF MACROMOLECULES TO LYSOSOMES (Hsiang-Kuang Lee and Louis Marzella). PASSIVE DIFFUSION ACROSS THE LYSOSOME MEMBRANE ( John Lloyd). VACUOLES OF PLANTS AND FUNGI (John-Michael Idriss).

Extracellular loops of BtuB facilitate transport of vitamin B12 through the outer membrane of E. coli.

Abstract: Vitamin B12 (or cobalamin) is an enzymatic cofactor essential both for mammals and bacteria. However, cobalamin can be synthesized only by few microorganisms so most bacteria need to take it up from the environment through the TonB-dependent transport system. The first stage of cobalamin import to E. coli cells occurs through the outer-membrane receptor called BtuB. Vitamin B12 binds with high affinity to the extracellular side of the BtuB protein. BtuB forms a β-barrel with inner luminal domain and extracellular loops. To mechanically allow for cobalamin passage, the luminal domain needs to partially unfold with the help of the inner-membrane TonB protein. However, the mechanism of cobalamin permeation is unknown. Using all-atom molecular dynamics, we simulated the transport of cobalamin through the BtuB receptor embedded in an asymmetric and heterogeneous E. coli outer-membrane. To enhance conformational sampling of the BtuB loops, we developed the Gaussian force-simulated annealing method (GF-SA) and coupled it with umbrella sampling. We found that cobalamin needs to rotate in order to permeate through BtuB. We showed that the mobility of BtuB extracellular loops is crucial for cobalamin binding and transport and resembles an induced-fit mechanism. Loop mobility depends not only on the position of cobalamin but also on the extension of luminal domain. We provided atomistic details of cobalamin transport through the BtuB receptor showing the essential role of the mobility of BtuB extracellular loops. A similar TonB-dependent transport system is used also by many other compounds, such as haem and siderophores, and importantly, can be hijacked by natural antibiotics. Our work could have implications for future delivery of antibiotics to bacteria using this transport system.

Immunohistochemical quantification of the cobalamin transport protein, cell surface receptor and Ki-67 in naturally occurring canine and feline malignant tumors and in adjacent normal tissues

Abstract: Cancer cells have an obligate need for cobalamin (vitamin B12) to enable DNA synthesis necessary for cellular replication. This study quantified the immunohistochemical expression of the cobalamin transport protein (transcobalamin II; TCII), cell surface receptor (transcobalamin II-R; TCII-R) and proliferation protein (Ki-67) in naturally occurring canine and feline malignant tumors, and compared these results to expression in corresponding adjacent normal tissues. All malignant tumor tissues stained positively for TCII, TCII-R and Ki-67 proteins; expression varied both within and between tumor types. Expression of TCII, TCII-R and Ki-67 was significantly higher in malignant tumor tissues than in corresponding adjacent normal tissues in both species. There was a strong correlation between TCII and TCII-R expression, and a modest correlation between TCII-R and Ki-67 expression in both species; a modest association between TCII and Ki-67 expression was present in canine tissues only. These results demonstrate a quantifiable, synchronous up-regulation of TCII and TCII-R expression by proliferating canine and feline malignant tumors. The potential to utilize these proteins as biomarkers to identify neoplastic tissues, streamline therapeutic options, evaluate response to anti-tumor therapy and monitor for recurrent disease has important implications in the advancement of cancer management for both human and companion animal patients.

Two-step activation prodrugs: transplatin mediated binding of chemotherapeutic agents to vitamin B12

Abstract: Clinically approved organic chemotherapeutic drugs such as cytarabine, dacarbazine and anastrozole were attached to B12via a {CN-trans-Pt(NH3)2}-bridge to yield [{Co}-CN-{trans-Pt(NH3)2}-{drug}]2+. The active organic drugs are protected by the platinum complex and by B12, which represents at the same time the targeting vector. We refer to these bioconjugates as two-step activation prodrugs since two reactions are finally required to liberate the actual organic drugs. All three prodrugs are soluble and stable in water. The physiological stability and the therapeutic efficiency of [{Co}-CN-{trans-Pt(NH3)2}-{cytarabine}]2+ (2) were studied. Under physiological conditions, 2 is stable for 3 days. Its affinity to the cobalamin transport proteins (haptocorrin, intrinsic factor and transcobalamin) is not substantially affected despite the introduction of a bulky group in the β-axial position. The cleavage of the [trans-CN-Pt(NH3)2-{cytarabine}]+ complex was observed upon chemical reduction of CoIII → CoII with Zn0. Cytarabine was subsequently released from the cleaved complex to exhibit its cytotoxicity. 2 displayed a reduced cytotoxicity (IC50 = 230 ± 62 nM) as compared to cytarabine (IC50 = 30 ± 5 nM). However, cytarabine released from 2 showed comparable cytotoxicity (IC50 = 30 ± 11 nM).