CDF family

Figure 8.12 An overview of zinc transport and trafficking in the yeast S. cerevisiae. Zip family transporters are in blue, CDF family transporters are in red and other transporters are in grey. (From Eide, 2006. Copyright 2006, with permission from Elsevier.)...

As we saw in Chapter 7, zinc uptake in plants involves proteins of the ZIP family, some of which are root specific while others are found in both roots and shoots. The transport of zinc from the cytosol in many organisms is often associated with members of the cation diffusion facility (CDF) family. Although there are 12 predicted family members in Arabidopsis, only one, MTP1, has been characterized, which seems to function in the transport of Zn into the vacuole. Two members of the heavy metal ATPase (HMA) family, HMA2 and HMA4, have been shown to function in the transport of zinc out of the cells across the plasma membrane. 

As we saw in Chapter 7, there are several plasma membrane zinc uptake transporters in yeast. Within the cell, a number of other proteins are involved in zinc transport within the cell. S. cerevisiae is unusual in that it does not appear to have any plasma membrane zinc efflux transporters. This is to a large extent compensated by the capacity of the vacuole to serve as a major site of zinc sequestration and detoxification, enabling wild-type cells to tolerate exogenous zinc concentrations as high as 5 mM. The zinc stored in the vacuole can attain millimolar levels, and can be mobilised under zinc-deficient conditions for use by the cell. Vacuolar zinc uptake is mediated by two members of the cation diffusion facility CDF family, Zrcl and Cotl (Fig. 8.16). 

For Zn(II) export, there are at least 3 membrane transporters that have been identified in E. coli. ZntA, the high specificity Zn(II) efflux pump, is transcriptionally-regulated by ZntR, a MerR homolog that binds Zn(II) (79-27). ZitB is a member of the cation diffusion facilitator (CDF) family that is specifically induced by Zn(U) (22) however, it is not clear if this transporter is specific only for Zn(II). A second CDF exporter, YiiP, is also present in E. coli, and a recent crystal structure on this exporter revealed details about how Zn(II) binds 23). Although work still remains to be performed to fully understand how... 

Of the heavy metal efflux systems, the CDF family predominates in all prokaryotic phyla examined, but the CadD family is well represented in Gram (+) bacteria (Table 4.11). CadD family members are not present in Gram (-) bacteria. On the other hand, within the RND superfamily. Heavy Metal Exporters (HME family) are well represented in Gram (-) but not in Gram (H-) bacteria. Neither family is represented in archaea. Thus, the CadD and HME families appear to occur in restricted prokaryotic phyla. Only one, but not both, is present in any one type of organisms (Table 4.11). 

Figure 2 Cellular zinc homeostasis. Zinc is delivered to the cytoplasm from either the extracellular space or vesicles within the cell by members of the ZIP family of transporters. A rise in cellular zinc results in activation and nuclear translocation of MTF-1. In the nucleus, MTF-1 regulates the transcription of a set of target genes, including MT and ZnT-1. MT will bind zinc, and ZnT-1 will transport zinc out across the plasma membrane. MT may govern the delivery of zinc to other proteins within the cell. Other members of the CDF family transport zinc into vesicles.

Polybrominated Biphenyls. A recent study has used caffeine as a potential tool to characterize exposure and/or effect of PBBs (Lambert et al. 1990). In this test, caffeine is used as a metabolic probe of cytochrome P-450 isozymes activity from the CYPIA family, which in animals is significantly induced by PBBs (Safe 1984). Tire caffeine breath test (CBT) is primarily useful for detecting induction of CYP1A2 activity in human liver, and for that reason, it also has been used as a marker for exposure to PCBs, CDDs, and CDFs (Lambert et al. 1992). A volunteer population of 50 Michigan subjects with previously high serum PBB levels and 50 with undetectable or low serum levels was compared to a control population not exposed to PBBs (Lambert et al. 1992). Two tests were conducted, the CYP1A2-dependent caffeine... 

FIGURE 7.16 Predicted membrane topologies for the ZIP/SLC39 and CDF/Znt/SLC30 families of metal ion transporters (a) Z1P/SLC39 (b) CDF/Znt/SLC30. (Fmm Eide, 2006. Copyright 2006 with permission from Elsevier.)... 

Patterson, P. H., The emerging neuropoietic cytokine family first CDF/LIF, CNTF and IL-6 next ONC, MGF, GCSF , Curr. Opin. Cell Biol., 2, 94, 1992. 

Dioxins are a family of heterocyclic hydrocarbons, mostly poisonous chemical by-products of the manufacture of certain herbicides and bactericides. The most toxic are polychlorinated dibenzo-p-dioxins (CDDs) and dibenzo-furans (CDFs, also called dioxins) [514,515]. Amongst the most dangerous are the isomers of the 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD) and 2,3,7,8-tetrachlorodibenzo-furan (TCDF). The former occurs in small amounts in some herbicides and defoliants, including the so-called Agent Orange (a highly toxic herbicide sprayed as a defoliant in chemical warfare) [466]. 

Interestingly, if organisms contain non-Bi2 cobalt enzymes such as nitrilases (Koba-yashi and Shimizu 1998), an additional slow, chemisosmotically driven uptake system (NiCoT protein family) is co-expressed with the enzyme (Komeda et al. 1997). ATP-hydrolyzing uptake systems for cobalt (e.g., ABC-transport systems) are not known. This indicates that cobalt for B12-enzymes may indeed be imported as cobalamin, Co(II) for other enzymes by NiCoT transport systems and that Co(II)-import by other systems may not be important in the natural environment of the cells. Co(II) is of medium toxicity and is detoxified by efflux systems (CDF protein family, RND-driven CBA-export systems) in bacteria and yeasts (Nies 2003). 

CDF/LIF levels are elevated in various inflammatory body fluids (Lotz et al., 1992 Waring et al., 1992 Hamilton et al., 1993 Alexander et al., 1994 Waring et al., 1994a,b). CDF/LIF is produced in articular tissues, and is also detected in synovial joint fluid in patients with rheumatoid arthritis (Lotz et al, 1992). Acute phase proteins are induced by the members of the lL-6 family (Richards et al, 1992 Mayer et al, 1993) and these proteins may play a role in the pathogenesis of rheumatoid arthritis (Blackburn, 1994). CDF/LIF is also present during acute rejection in the urine of kidney graft patients (Taupin et al,... 

CDF/LIF, identified only relatively recently, has become one of the most extensively studied cytokines and turned out to play a remarkable varietyof roles in living organisms. Recent advances in molecular and cellular biological studies of CDF/LIF reveal that this factor has at least three important specific functions in vivo. First, it is essential for blastocyst implantation. Second, it is required for self-renewal of a group of myeloid stem cells. Third, it probably functions as a repair factor following nerve injury and in some host defence systems. It remains, however, unknown in what manner CDF/LIF, as a member of the EL-6 family, interacts with other cytokines and growth factors to fulfil these and other complex physiological functions. 

Synthetic Studies Toward Saframycin B and Ecteinascidin 743 (Yondelis) Tetrahy-droisoquinoline alkaloids are a broad family of biologically active natural products. Takemoto et al. [39] have carried out a concise synthesis of the CDF ring system present in this kind of alkaloids (Scheme 2.36). Both An(I)-catalyzed intramolecnlar hydroamination of alkynyl amide and NBS-mediated oxidative FC cyclization were utilized as key reactions. By rednctive alkylation of a-amino acid derivative 235 with aldehyde 236, the conpling prodnct 237 was obtained... 

Heavy metal ions are both essential for life and toxic at high concentrations. Eight families of secondary active transporters are known to mediate divalent cation uptake and/or efflux (Nramp, VIT, ZIP, and NiCoT for uptake and CaCA, CDF, CadD, and RND/HME for efflux). In LAB, two of... 

Protein families involved in vacuolar sequestration may be the NRAMP s, CDF s, and CAX s (reviewed by Hall and Williams [102]) as well as CPx-type ATPases. Until now, already several transporters for vacuolar sequestration of zinc (and possibly cadmium) and nickel have been investigated and could be partially characterized [103-107]. Several CDF transporters for vacuolar sequestration of Zn (and possibly Cd and Co) have been characterized, all are homologous, almost identical in sequence. These are MTPl, ZAT, and ZTP (e.g., [88,89,103,108]). The strongly elevated expression of the CPx-type metal ATPase HMA3 was shown to play a decisive role in Cd accumulation not only in T. caerulescens [109], but also in rice [110,111], reconfirming also the importance of the sequestration into vacuoles for the hyperaccumulation phenotype. The natural over-expression of NRAMPs was identified both in rice and in T. caerulescens to play an important role in Cd tolerance and possibly Cd accumulation [112-114]. When vacuolar... 

Figure 4.4 Energy diagram of CdF. Vertical excitation energy of the CdF electronic state and family label. Fhe ordinate denotes the vertical excitation energy in eV. The abscissa denotes the Q value. Only positive values of FI are treated. Solid circles and solid lines denote families having the same Q as the X family. Open squares and broken lines denote families with FI differing from the X family. See color plate section...

---