zinc is an essential trace element for living organisms , because it is required for the catalytic activity of numerous metalloenzymes ( 1 ) and can also serve as a key structural component of a large number of zinc - dependent proteins 2 . , 3 .. zinc homeostasis in the cells , therefore , is achieved through the coordinate regulation of zinc influx , efflux , and distribution to intracellular organelles ( 4 ) . zinc transporters have essential functions in such processes and a number of zinc transporters have been identified in many organisms 4 . , 5 . , 6 . , 7 .. zinc transporters are largely classified into two metal transporter families , the zip ( zrt / irt - like protein ) and cdf ( cation diffusion facilitator ) families 4 . , 5 . , 7 .. in bacteria , the abc transporters and p - type atpases have been shown to function as zinc transporters ( 8) , but neither of them plays a physiological role in zinc transport in eukaryotes ( 5 ) . the zip and cdf families are also assigned as solute carrier 39 ( slc39a ) and slc30a families 9 . both seem to have a very ancient origin because they are identified in diverse organisms from archeae and eubacteria to eukaryotes ( 5 ) . zip family transporters function in zinc influx into the cytosol , while cdf family transporters mobilize zinc in the opposite direction . all members of both families are thought to transport zinc across the biological membranes , but certain proteins are speculated to transport other metals such as iron , nickel , and manganese as a major substrate . in fact , zip and cdf transporters have been shown to transport these metals as physiologically important substrates in certain plants 11 . manganese not zinc is described as a more selective substrate of zip8/bigm103 in the competitive assay of cadmium uptake ( 14 ) . recently , interesting functions of zip and cdf transporters have been found in various organisms . a comprehensive deliberation on these functions together with integrative comparison of the sequence similarity within each zip and cdf transporter family would provide a clue to speculate functions of the uncharacterized zip and cdf proteins and to elicit further functions of the characterized ones . here we review the physiological and cellular functions of zip and cdf transporters with emphasis on these matters . to date , fourteen zip proteins have been molecularly characterized or identified in human and mouse 4 . , 9 .. the zip family is divided into subfamilies i , ii , liv1/lzt , and gufa , based on their degrees of sequence conservation 5 . the liv1/lzt subfamily is characterized by having a metalloprotease motif ( hexphexgd ) around the membrane - spanning domain v. although the initial histidine in the hexphexgd motif is thought to be requisite for the zinc transport activity of liv1/lzt transporters , zip8/bigm103 and zip14 lacking it have zinc transport activity 19 . , 22 .. zip proteins are predicted to have eight membrane - spanning domains with a membrane topology in which the n- and c - terminal ends are located outside the plasma membrane , and have a cytoplasmic his - rich loop between membrane - spanning domains iii and iv , which is thought to function as a zinc - binding site . however , zip11 , zip12 , and zip13 lack the his - rich loop . table 1 shows the zip proteins found in the genome sequences of human , mouse , chicken , zebrafish , fruit fly , nematode , and yeast according to the similarity to the human zip proteins . as shown in table 1 , most liv1/lzt proteins in the indicated organisms are arranged to each human liv1/lzt member except in yeast , where the liv1/lzt protein is only found as the homologous protein to zip7/ke4 . in liv1/lzt subfamily , zip12 and zip4 , zip8/bigm103 and zip14 , zip10 and zip6/liv1 , or zip13 and zip7/ke4 are similar ( figure 1 ) , but not completely homologous . for example , zip12 lacks the his - rich loop between membrane - spanning domains iii and iv while zip4 has ; zip13 lacks histidine residues in n - terminal portion and between membrane - spanning domains ii and iii , or iii and iv , but zip7/ke4 has many histidine residues in these portions . zip8/bigm103 and zip14 , or zip10 and zip6/liv1 have a high identity ( 48% or 38% identity , respectively ) and are homologous in the length of amino acid sequence , the property of the his - rich loop , and the distribution of histidine residues in their sequences 19 . , 23 .. the expression of only one or the other of zip8/bigm103 and zip14 in nematode , or zip10 and zip6/liv1 in fruit fly and nematode , may be sufficient for the biological function , judging from the genome sequences ( table 1 ) . compared with liv1/lzt subfamily , zipii subfamily has similar amino acid length , topology , and subcellular localization ( at the plasma membrane ) 4 . , 5 . , 24 .. interestingly , the numbers of homologous proteins of zip1 , zip2 , or zip3 found are : one in chicken and zebrafish , two in yeast , and six in nematode ( table 1 ) , which may be linked to the fact that nematode has extra cdf proteins ( see table 2 and below ) . all eukaryotes have proteins with similarity to zip9 of zipi subfamily or zip11 of gufa subfamily , which suggests that they may have retained important functions during evolution . zebrafish zip6/liv1 is essential for epithelial - mesenchymal transition ( emt ) , which is one of the central events of embryonic development , organ and tissue remodeling , and cancer metastasis , by regulating the nuclear localization of the zinc - finger transcription factor snail , a master regulator of emt , because it represses the transcription of e - cadherin ( 25 ) . the expression of zebrafish zip6/liv1 is dependent on stat3 , which is required for the cell migration , and this characteristic is conserved in human and mouse zip6/liv1 ( 25 ) . as zip6/liv1 was identified as an estrogen - regulated gene in breast cancer cells ( 26 ) and was shown to be significantly associated with the spread of breast cancer to the lymph nodes ( 27 ) , the presented function of zip6/liv1 is very interesting in that it may be a novel therapeutic target for improving tumor therapy ( 28 ) . foi , a homologous protein of zip10 in fruit fly , can act as a zinc transporter ( 29 ) , and is required for both germ cell ensheathment and gonad morphogenesis in order to control germ cell migration without affecting gonad cell identity ( 30 ) . it controls the level of e - cadherin in the gonad that is essential for the cell - cell adhesion ( 31 ) . foi was reported as the closely related protein to zip6/liv1 ( 30 ) , but its sequence is the most homologous to zip10 ( table 1 ) . zip10 and zip6/liv1 are homologous in amino acid sequence ( 38% identity ) and the property of many histidine residues in the his - rich loop or n - terminal portion , therefore they are likely to have very similar functions . another liv1/lzt protein , catsup , a fruit fly zip7/ke4 orthologue , down - regulates tyrosine hydroxylase activity ( 32 ) . interestingly , iar1 , an arabidopsis zip7/ke4 homologue , is supposed to regulate auxin conjugate hydroxylase activity by exporting inhibitory metal ( zinc ) out of the secretory pathway ( 33 ) . actually , zip7/ke4 is localized to the endoplasmic reticulum ( er ) and the golgi apparatus 34 . , 35 . and transport zinc out of the golgi apparatus ( 35 ) . since the expression of mouse zip7/ke4 cdna complements the defects of iar1 mutant ( 33 ) , zip7/ke4 and all of its orthologues may export zinc out of the secretory compartments to fine - tune the activity of zinc - requiring enzymes and other metal - requiring enzymes like hydroxylases . in yeast , a high - affinity zinc uptake transporter , zrt1 , is rapidly endocytosed from plasma membrane through a ubiquitin - mediated mechanism and degraded in vacuoles in response to high levels of extracellular zinc 36 . , 37 .. this type of posttranslational distribution operates in mammalian zip proteins ; not only in the zrt1 homologous proteins zip1 and zip3 38 . , 39 . , 41 .. these characteristics of zip transporters indicate that the traffic of zip proteins in response to extracellular zinc would be essential for physiological and cellular zinc homeostasis . to date , fourteen zip proteins have been molecularly characterized or identified in human and mouse 4 . , 9 .. the zip family is divided into subfamilies i , ii , liv1/lzt , and gufa , based on their degrees of sequence conservation 5 . the liv1/lzt subfamily is characterized by having a metalloprotease motif ( hexphexgd ) around the membrane - spanning domain v. although the initial histidine in the hexphexgd motif is thought to be requisite for the zinc transport activity of liv1/lzt transporters , zip8/bigm103 and zip14 lacking it have zinc transport activity 19 . , 22 .. zip proteins are predicted to have eight membrane - spanning domains with a membrane topology in which the n- and c - terminal ends are located outside the plasma membrane , and have a cytoplasmic his - rich loop between membrane - spanning domains iii and iv , which is thought to function as a zinc - binding site . however , zip11 , zip12 , and zip13 lack the his - rich loop . table 1 shows the zip proteins found in the genome sequences of human , mouse , chicken , zebrafish , fruit fly , nematode , and yeast according to the similarity to the human zip proteins . as shown in table 1 , most liv1/lzt proteins in the indicated organisms are arranged to each human liv1/lzt member except in yeast , where the liv1/lzt protein is only found as the homologous protein to zip7/ke4 . in liv1/lzt subfamily , zip12 and zip4 , zip8/bigm103 and zip14 , zip10 and zip6/liv1 , or zip13 and zip7/ke4 are similar ( figure 1 ) , but not completely homologous . for example , zip12 lacks the his - rich loop between membrane - spanning domains iii and iv while zip4 has ; zip13 lacks histidine residues in n - terminal portion and between membrane - spanning domains ii and iii , or iii and iv , but zip7/ke4 has many histidine residues in these portions . zip8/bigm103 and zip14 , or zip10 and zip6/liv1 have a high identity ( 48% or 38% identity , respectively ) and are homologous in the length of amino acid sequence , the property of the his - rich loop , and the distribution of histidine residues in their sequences 19 . , 23 .. the expression of only one or the other of zip8/bigm103 and zip14 in nematode , or zip10 and zip6/liv1 in fruit fly and nematode , may be sufficient for the biological function , judging from the genome sequences ( table 1 ) . compared with liv1/lzt subfamily , zipii subfamily has similar amino acid length , topology , and subcellular localization ( at the plasma membrane ) 4 . , 5 . , 24 .. interestingly , the numbers of homologous proteins of zip1 , zip2 , or zip3 found are : one in chicken and zebrafish , two in yeast , and six in nematode ( table 1 ) , which may be linked to the fact that nematode has extra cdf proteins ( see table 2 and below ) . all eukaryotes have proteins with similarity to zip9 of zipi subfamily or zip11 of gufa subfamily , which suggests that they may have retained important functions during evolution . zebrafish zip6/liv1 is essential for epithelial - mesenchymal transition ( emt ) , which is one of the central events of embryonic development , organ and tissue remodeling , and cancer metastasis , by regulating the nuclear localization of the zinc - finger transcription factor snail , a master regulator of emt , because it represses the transcription of e - cadherin ( 25 ) . the expression of zebrafish zip6/liv1 is dependent on stat3 , which is required for the cell migration , and this characteristic is conserved in human and mouse zip6/liv1 ( 25 ) . as zip6/liv1 was identified as an estrogen - regulated gene in breast cancer cells ( 26 ) and was shown to be significantly associated with the spread of breast cancer to the lymph nodes ( 27 ) , the presented function of zip6/liv1 is very interesting in that it may be a novel therapeutic target for improving tumor therapy ( 28 ) . foi , a homologous protein of zip10 in fruit fly , can act as a zinc transporter ( 29 ) , and is required for both germ cell ensheathment and gonad morphogenesis in order to control germ cell migration without affecting gonad cell identity ( 30 ) . it controls the level of e - cadherin in the gonad that is essential for the cell - cell adhesion ( 31 ) . foi was reported as the closely related protein to zip6/liv1 ( 30 ) , but its sequence is the most homologous to zip10 ( table 1 ) . zip10 and zip6/liv1 are homologous in amino acid sequence ( 38% identity ) and the property of many histidine residues in the his - rich loop or n - terminal portion , therefore they are likely to have very similar functions . either of them may function as a backup system if expressed simultaneously . another liv1/lzt protein , catsup , a fruit fly zip7/ke4 orthologue , down - regulates tyrosine hydroxylase activity ( 32 ) . interestingly , iar1 , an arabidopsis zip7/ke4 homologue , is supposed to regulate auxin conjugate hydroxylase activity by exporting inhibitory metal ( zinc ) out of the secretory pathway ( 33 ) . actually , zip7/ke4 is localized to the endoplasmic reticulum ( er ) and the golgi apparatus 34 . , 35 . and transport zinc out of the golgi apparatus ( 35 ) . since the expression of mouse zip7/ke4 cdna complements the defects of iar1 mutant ( 33 ) , zip7/ke4 and all of its orthologues may export zinc out of the secretory compartments to fine - tune the activity of zinc - requiring enzymes and other metal - requiring enzymes like hydroxylases . in yeast , a high - affinity zinc uptake transporter , zrt1 , is rapidly endocytosed from plasma membrane through a ubiquitin - mediated mechanism and degraded in vacuoles in response to high levels of extracellular zinc 36 . , 37 .. this type of posttranslational distribution operates in mammalian zip proteins ; not only in the zrt1 homologous proteins zip1 and zip3 38 . , 39 . , 41 .. these characteristics of zip transporters indicate that the traffic of zip proteins in response to extracellular zinc would be essential for physiological and cellular zinc homeostasis . to date , ten cdf proteins designated as znt ( zn transporter ) proteins of human or murine origin have been molecularly characterized or identified 7 . , 10 . , 42 .. cdf transporters are divided into three subgroups , cdf subfamilies i , ii , and iii , based on their sequence similarities ( 5 ) . most eukaryotic members are assigned to subfamilies ii and iii ( 5 ) but znt9/huel and its homologous proteins are classified into cdf subfamily i ( figure 1 ) , which contains mostly prokaryotic members from both eubacterial and archeael sources ( 5 ) . there are sequence similarities among znt2 , znt3 , znt4 , and znt8 , between znt1 and znt10 , and between znt5 and znt7 ( figure 1 ) , which suggests that these closely related proteins have similar functions in the cells . cdf transporters have the same predicted membrane topology of six membrane - spanning domains with both n- and c - terminal ends thought to reside intracellularly and a cytoplasmic his - rich loop between membrane - spanning domains iv and v , although znt5 and its homologous proteins have a long n - terminal portion with extra membrane - spanning domains ( 43 ) . in znt6 and its orthologues , the his - rich loop is not rich in histidine residues but retains serine residues instead ( 44 ) . in znt10 and its orthologues , the loop lacks histidine residues but bears a long loop rich in serine and basic amino acid residues ( 42 ) . the his - rich loop is thought to function as a metal - binding site and is shown to have essential functions ( 45 ) . znt9/huel has a cation efflux domain ( pfam01545 ) ; therefore , it has been assigned to the cdf family 7 . , 10 .. however , znt9/huel and its homologous proteins have significant homology to the dna - binding domain and the nuclear receptor interaction motif ( 46 ) . furthermore , znt9/huel is predominantly localized to the cytoplasm and translocates to the nucleus in a cell cycle - dependent manner ( 46 ) . the cdf proteins found in the human , mouse , chicken , zebrafish , fruit fly , nematode , and yeast genome sequences are arranged in table 2 according to the similarity to human znt proteins as in table 1 . compared with zip proteins , cdf proteins in the indicated organisms are arranged to each human znt member except for znt3 . znt3 is specifically expressed in the brain , which suggests that znt3 has important neural functions in mammals ( 47 ) . since the zinc transported by znt3 into the synaptic vesicles is implicated in -amyloid plaque formation ( 48 ) , the expression level of znt3 may be an important factor in the incidence of alzheimer s disease . the sequences of znt5 and znt6 are found simultaneously in all organisms except for fruit fly ( table 2 ) , which is consistent with their characteristic to form hetero - oligomeric complexes ( 49 ) . in fruit fly , the znt7 homologous protein is found ( table 2 ) . as znt5 and znt7 have similar functions in the secretory pathway ( see below and ref . 45 ) , the expression of either znt5 ( with znt6 ) or znt7 would be sufficient in fruit fly , nematode , and yeast . mft1 and mft2 , which were identified as mitochondrial iron transporters in yeast ( 50 ) , and sur7 , which is the nematode cdf protein involved in ras signaling ( 51 ) , are not classified into human members because of low homology and different subcellular localization and functions ( table 2 ) . nematode has five more cdf proteins that fail to show similarity to human members ( table 2 ) . further investigation is needed to identify their functions and the relationship between these unclassified cdf proteins and mammalian members . like the zip proteins , interesting cdf functions have been found in the model organisms . in yeast , msc2 and zrg17 form hetero - oligomeric complexes and have essential functions to maintain homeostasis in the er by transporting zinc into the er ( 52 ) . they are counterpart proteins of znt5 and znt6 , although msc2 is homologous to znt5 only in the c - terminal portion including six membrane - spanning domains 43 . , 53 . and zrg17 is the distant homologue of znt6 ( 52 ) . the hetero - oligomeric formation of znt5 and znt6 has been evidenced by using chicken dt40 cells deficient in znt5 , znt6 , and znt7 ( 49 ) . znt7 is homologous to znt5 in cation efflux domains ( pfam01545 ) , but it fails to form hetero - oligomeric complexes with znt6 ( unpublished data ) , instead , it forms homo - oligomeric complexes ( 49 ) . in vertebrates , these two different zinc transport complexes , znt5/znt6 hetero - oligomeric complexes and znt7 homo - oligomeric complexes , operate to activate zinc - requiring enzymes like alkaline phosphatases that are synthesized and activated by binding with zinc in the secretory pathway ( 49 ) . moreover , since msc2 and zrg17 are involved in the unfolded protein response ( upr ) because the mutant yeast strains lacking neither or either of the genes are defective in the er - associated degradation ( erad ) and show the increased upr under low - zinc conditions 52 . in fact , zinc deficiency can up - regulate the upr in mammalian cells ( 54 ) . cdf1 , a nematode znt1 orthologue , positively regulates the ras - raf - mek - erk signal transduction by promoting zinc efflux and reducing the concentration of cytosolic zinc 55 . , 56 .. cdf1 binds to raf-1 and promotes the biological and enzymatic activity of raf-1 ( 57 ) . this interaction occurs between the intracellular c - terminal tail of cdf1 and the n - terminal regulatory portion of raf-1 . , 57 .. as the binding of znt1 to raf-1 is inhibited by zinc ( 57 ) , it is plausible that znt1 lowers the cytosolic zinc , which promotes its binding to raf-1 and facilitates raf-1 activation . however , it has not been elucidated whether the mammalian ras - mediated signaling pathway is fine - tuned by znt1 in physiological condition . the divergent cdf protein in nematode , sur7 , which is probably localized to the er , also positively regulates ras signaling through modulating the activity of kinase suppressor of ras ( ksr ; ref . in fact , the toc-1 protein ( zc395.3 ) that shows homology to znt6 is reported to be involved in ras signaling ( 51 ) . the toc-1 protein seems to have essential functions of supplying zinc to proteins in the secretory pathway by forming hetero - oligomeric complexes with the znt5 orthologue protein ( y105e8a.3 ) , because the znt7 gene is not found in the nematode genome sequence ( table 2 ) . the putative hetero - oligomeric complexes may have important functions in ras signaling in nematode . to date , ten cdf proteins designated as znt ( zn transporter ) proteins of human or murine origin have been molecularly characterized or identified 7 . , 10 . , 42 .. cdf transporters are divided into three subgroups , cdf subfamilies i , ii , and iii , based on their sequence similarities ( 5 ) . most eukaryotic members are assigned to subfamilies ii and iii ( 5 ) but znt9/huel and its homologous proteins are classified into cdf subfamily i ( figure 1 ) , which contains mostly prokaryotic members from both eubacterial and archeael sources ( 5 ) . there are sequence similarities among znt2 , znt3 , znt4 , and znt8 , between znt1 and znt10 , and between znt5 and znt7 ( figure 1 ) , which suggests that these closely related proteins have similar functions in the cells . cdf transporters have the same predicted membrane topology of six membrane - spanning domains with both n- and c - terminal ends thought to reside intracellularly and a cytoplasmic his - rich loop between membrane - spanning domains iv and v , although znt5 and its homologous proteins have a long n - terminal portion with extra membrane - spanning domains ( 43 ) . in znt6 and its orthologues , the his - rich loop is not rich in histidine residues but retains serine residues instead ( 44 ) . in znt10 and its orthologues , the loop lacks histidine residues but bears a long loop rich in serine and basic amino acid residues ( 42 ) . the his - rich loop is thought to function as a metal - binding site and is shown to have essential functions ( 45 ) . znt9/huel has a cation efflux domain ( pfam01545 ) ; therefore , it has been assigned to the cdf family 7 . , 10 .. however , znt9/huel and its homologous proteins have significant homology to the dna - binding domain and the nuclear receptor interaction motif ( 46 ) . furthermore , znt9/huel is predominantly localized to the cytoplasm and translocates to the nucleus in a cell cycle - dependent manner ( 46 ) . the cdf proteins found in the human , mouse , chicken , zebrafish , fruit fly , nematode , and yeast genome sequences are arranged in table 2 according to the similarity to human znt proteins as in table 1 . compared with zip proteins , cdf proteins in the indicated organisms are arranged to each human znt member except for znt3 . znt3 is specifically expressed in the brain , which suggests that znt3 has important neural functions in mammals ( 47 ) . since the zinc transported by znt3 into the synaptic vesicles is implicated in -amyloid plaque formation ( 48 ) , the expression level of znt3 may be an important factor in the incidence of alzheimer s disease . the sequences of znt5 and znt6 are found simultaneously in all organisms except for fruit fly ( table 2 ) , which is consistent with their characteristic to form hetero - oligomeric complexes ( 49 ) . in fruit fly , the znt7 homologous protein is found ( table 2 ) . as znt5 and znt7 have similar functions in the secretory pathway ( see below and ref . 45 ) , the expression of either znt5 ( with znt6 ) or znt7 would be sufficient in fruit fly , nematode , and yeast . mft1 and mft2 , which were identified as mitochondrial iron transporters in yeast ( 50 ) , and sur7 , which is the nematode cdf protein involved in ras signaling ( 51 ) , are not classified into human members because of low homology and different subcellular localization and functions ( table 2 ) . nematode has five more cdf proteins that fail to show similarity to human members ( table 2 ) . further investigation is needed to identify their functions and the relationship between these unclassified cdf proteins and mammalian members . like the zip proteins , interesting cdf functions have been found in the model organisms . in yeast , msc2 and zrg17 form hetero - oligomeric complexes and have essential functions to maintain homeostasis in the er by transporting zinc into the er ( 52 ) . they are counterpart proteins of znt5 and znt6 , although msc2 is homologous to znt5 only in the c - terminal portion including six membrane - spanning domains 43 . , 53 . the hetero - oligomeric formation of znt5 and znt6 has been evidenced by using chicken dt40 cells deficient in znt5 , znt6 , and znt7 ( 49 ) . znt7 is homologous to znt5 in cation efflux domains ( pfam01545 ) , but it fails to form hetero - oligomeric complexes with znt6 ( unpublished data ) , instead , it forms homo - oligomeric complexes ( 49 ) . in vertebrates , these two different zinc transport complexes , znt5/znt6 hetero - oligomeric complexes and znt7 homo - oligomeric complexes , operate to activate zinc - requiring enzymes like alkaline phosphatases that are synthesized and activated by binding with zinc in the secretory pathway ( 49 ) . moreover , since msc2 and zrg17 are involved in the unfolded protein response ( upr ) because the mutant yeast strains lacking neither or either of the genes are defective in the er - associated degradation ( erad ) and show the increased upr under low - zinc conditions 52 . in fact , zinc deficiency can up - regulate the upr in mammalian cells ( 54 ) . cdf1 , a nematode znt1 orthologue , positively regulates the ras - raf - mek - erk signal transduction by promoting zinc efflux and reducing the concentration of cytosolic zinc 55 . , 56 .. cdf1 binds to raf-1 and promotes the biological and enzymatic activity of raf-1 ( 57 ) . this interaction occurs between the intracellular c - terminal tail of cdf1 and the n - terminal regulatory portion of raf-1 . , 57 .. as the binding of znt1 to raf-1 is inhibited by zinc ( 57 ) , it is plausible that znt1 lowers the cytosolic zinc , which promotes its binding to raf-1 and facilitates raf-1 activation . however , it has not been elucidated whether the mammalian ras - mediated signaling pathway is fine - tuned by znt1 in physiological condition . the divergent cdf protein in nematode , sur7 , which is probably localized to the er , also positively regulates ras signaling through modulating the activity of kinase suppressor of ras ( ksr ; ref . in fact , the toc-1 protein ( zc395.3 ) that shows homology to znt6 is reported to be involved in ras signaling ( 51 ) . the toc-1 protein seems to have essential functions of supplying zinc to proteins in the secretory pathway by forming hetero - oligomeric complexes with the znt5 orthologue protein ( y105e8a.3 ) , because the znt7 gene is not found in the nematode genome sequence ( table 2 ) . the putative hetero - oligomeric complexes may have important functions in ras signaling in nematode . various roles of zip or cdf transporters have been clarified , but further studies are needed to fully elucidate their physiological functions . a comprehensive comparison of similarities and differences in the functions and regulations in transcription , translation , trafficking , and turnover of homologous proteins of zip and cdf among mammals and other organisms should help elucidate the true role of each transporter in zinc homeostasis . by elucidating which of the redundant transporters is the principal or the backup , and identifying which transporter forms homo - oligomeric complexes or hetero - oligomeric complexes to express zinc transport activity , we should be able to ultimately solve the intriguing question why living organisms including humans need so many zinc transporters to survive .