Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “metal transporter”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2026

Systematic mining and characterization of metal transporter families regulating zinc homeostasis provide insights into metal homeostasis in Camellia sinensis.

BACKGROUND AND AIMS: Zinc is essential for tea plant growth and quality formation, yet its homeostatic mechanisms remain poorly understood. This study identified metal transporter families regulating zinc homeostasis, analyzed their evolution, structure, and expression, and clarified zinc uptake, transport, detoxification networks, and their links to metabolism. METHODS: This study identified zinc homeostasis-related metal transporter families in the tea plant genome, characterized their structural features and expression profiles across tissues and developmental stages through integrative bioinformatics and transcriptomic analyses, and delineated the molecular mechanisms underlying zinc uptake, translocation, and detoxification by systematically integrating published evidence. RESULTS: This study identified 74 metal transporter genes from six families: 13 CsZIPs, 12 CsNRAMPs, 10 CsHMAs, 10 CsYSLs, 14 CsMTPs, and 15 CsCAXs in the 'Shuchazao2' genome, revealing closer affinity to woody species than to Arabidopsis. These proteins exhibit conserved domains, diverse subcellular localizations (cell membrane, vacuole, chloroplast, and Golgi apparatus), and tissue-specific expression with abundant stress/hormone-responsive cis-elements. At the plant-soil interface, tea plants mobilize rhizospheric zinc via proton and organic acid secretion; CsYSLs, CsNRAMPs, and CsZIPs mediate zinc uptake, aided by arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) that expand root absorption zones. Xylem CsHMAs and phloem CsYSLs coordinate root-to-shoot zinc translocation, and vacuolar transporters (CsMTPs, CsCAXs), cell wall immobilization, and antioxidant systems alleviate high-zinc stress injury. CONCLUSIONS: These findings collectively delineate an integrated zinc "acquisition-distribution-buffering" network in tea plants, offering a repertoire of candidate genes with potential utility in zinc biofortification breeding and improving acid soil adaptation. Further experimental validation, including tea transgenesis, zinc-stress qRT-PCR, and heterologous functional complementation, is essential to substantiate their biological roles.

Camellia sinensis↗
PubMed1976

On the role of bacitracin peptides in trace metal transport by Bacillus licheniformis.

Bacitracin markedly increased the toxic effect of several divalent metal ions towards growth of the producer strain Bacillus licheniformis ATCCI4580. Magnesium ions antagonized the toxic effect of these divalent cations both in the presence and absence of bacitracin. It is suggested that bacitracin increases the uptake of several divalent metal ions. The function of the bacitracin peptides may be to extract essential divalent cations from 'waiting sites' on the surface of the cells and transfer the cations to the transport mechanisms in the cytoplasmic membrane.

Bacillus↗
PubMed2026

Functional screening of ZIP8 naturally occurring variants identifies pathogenic mutations and trafficking defects.

The rapid expansion of human genomic data has revealed a large number of naturally occurring variants, creating a major challenge for functional annotation. The human metal transporter SLC39A8 (ZIP8) is a clinically important divalent metal transporter, yet most of its documented variants remain uncharacterized. Here, we developed a workflow to functionally evaluate ZIP8 variants by integrating laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOF-MS) with scaled-up cell-based transport assays. Using this method, we systematically analyzed 33 naturally occurring missense variants located in the extracellular domain (ECD) of ZIP8. The assay enables direct quantification of intracellular metal accumulation with substantially improved throughput (∼150 samples per hour). Functional screening identified 14 potential pathogenic variants with significantly reduced transport activity. Comparison with computational predictions revealed a moderate correlation between activity and AlphaMissense pathogenicity scores (R2 = 0.423), while an error rate of ∼20% for AlphaMissense underscores the need for experimental validation. Flow cytometry analysis showed that most loss-of-function variants exhibit impaired trafficking of the protein to the cell surface possibly due to mutation-caused protein misfolding or instability. Structural mapping of activity-compromised variants, together with functional assessment of the ZIP8-ECD, highlights the importance of this domain in ZIP8 expression and intracellular protein trafficking. Together, this work establishes a scalable approach for functional screening of metal transporter variants and provides new insights into the structure-function relationships of ZIP8.

Journal Article↗
PubMed2026

Functional screening of ZIP8 naturally occurring variants identifies pathogenic mutations and trafficking defects.

The rapid expansion of human genomic data has revealed a large number of naturally occurring variants, creating a major challenge for functional annotation. The human metal transporter SLC39A8 (ZIP8) is a clinically important, promiscuous divalent metal transporter, yet most of its documented variants remain uncharacterized. Here, we developed a workflow to functionally evaluate ZIP8 variants by integrating laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOF-MS) with scaled-up cell-based transport assays. Using this method, we systematically analyzed 33 naturally occurring missense variants located in the extracellular domain (ECD) of ZIP8. The assay enables direct quantification of intracellular metal accumulation with substantially improved throughput (~150 samples per hour). Functional screening identified 14 potential pathogenic variants with significantly reduced transport activity. Comparison with computational predictions revealed a moderate correlation between activity and AlphaMissense pathogenicity scores (R2 = 0.423), while an error rate of ~20% underscores the need for experimental validation. Flow cytometry analysis showed that most loss-of-function variants exhibit impaired trafficking of the protein to the cell surface possibly due to mutation-caused protein misfolding or instability. Structural mapping of activity-compromised variants, together with functional assessment of the ZIP8-ECD, highlights the importance of this domain in ZIP8 expression and intracellular trafficking. Together, this work establishes a scalable approach for functional screening of metal transporter variants and provides new insights into the structure-function relationships of ZIP8.

Journal Article↗
PubMed2026

Silicon-mediated alleviation of mercury toxicity requires coordinated regulation of antioxidant defense, metal homeostasis, and nodule function in mung bean.

Mercury (Hg) contamination and accumulation in agricultural soil represent a major hazardous environmental concern, posing serious threats to living organisms, including plants. Silicon (Si) has been widely recognized to mitigate heavy metal (loid) toxicity; however, the underlying mechanism of Si-mediated mitigation of Hg-stress in mung bean remains unclear. In this study, we addressed this research gap by thoroughly examining the potential effects of Si supplementation on Hg-stressed mung bean plants, with particular emphasis on investigating the possible effects of Si on plant biomass, nodulation traits, antioxidant defense, and expression of metal-transporter and detoxification genes. Our findings demonstrated that Hg stress significantly impaired plant growth by inducing oxidative stress and reducing biological nitrogen fixation efficiency whereas Si application significantly alleviated the Hg-induced toxicity. Specifically, Si increased shoot dry biomass by +113% (2.13-fold), root dry biomass by +60% (1.60-fold), nodule number by +152% (2.52-fold), and nodule dry weight by +273% (3.73-fold) under Hg stress compared to Hg treated plants only. Furthermore, Si enhanced antioxidant defense system, restricted the uptake and accumulation of Hg in different plant tissues, and regulated the expression of genes related to metal transport and detoxification, contributing to improved nodulation and nitrogen fixation under Hg stress. Overall, our findings demonstrate that Si application mitigates the Hg-induced toxicity in mung bean plants by enhancing antioxidant defense, improving nitrogen fixation, regulation of genes involved in metal transport and detoxification, and limiting Hg accumulation.

Vigna radiata↗
PubMed2025

Analysis of novel zinc-binding proteins in the cell wall of Corynebacterium diphtheriae.

UNLABELLED: Zinc is a critical nutrient for all living organisms, including bacterial pathogens such as Corynebacterium diphtheriae, the causative agent of the severe human respiratory disease diphtheria. As such, zinc acquisition is essential for many pathogens to cause disease. We previously showed that the zinc-regulated ABC transporter encoded by the znu locus is one of several zinc uptake systems that support the growth of C. diphtheriae in zinc-limited medium. In this study, we examine the function and cellular localization of components encoded by the znu gene cluster, which includes the ZnuABC transporter and the novel membrane and cell wall proteins ZnuE, ZnuF, and ZnuG. Deletion of znuE results in reduced growth in zinc-limited media, suggesting a role in zinc uptake. While the growth of znuF and znuG mutants was not affected in zinc-limited medium, deletion of these two genes in a mutant also lacking the znuABC transporter restored growth to wild-type levels, suggesting that ZnuF and ZnuG exert an unusual modulating effect on zinc import. ZnuE, ZnuF, and ZnuG possess a unique motif that is associated with Zn binding as demonstrated by thermal shift assays, targeted mutagenesis, and structural analysis. Although ZnuF and ZnuG are both present in the cell wall, only ZnuG contains a sortase recognition signal that is critical for localizing proteins to the cell wall. Furthermore, ZnuF localization does not require any of the six known sortase enzymes in C. diphtheriae, suggesting a novel localization mechanism. IMPORTANCE: Zinc is a critical nutrient required by many bacterial pathogens. While the function of multiple zinc importer systems has been previously characterized in Corynebacterium diphtheriae, the transporter encoded by the znu gene cluster includes components not found in other metal transport systems. In this report, we examined the roles of three components of the znu gene cluster, ZnuE, ZnuF, and ZnuG, and show that these proteins all possess a putative zinc-binding domain and have varying effects on growth in zinc-limited medium. Additionally, ZnuF uses a novel mechanism for cell wall localization. This study further expands our understanding of C. diphtheriae zinc import and points to a potentially novel mechanism for the localization of cell wall proteins.

Corynebacterium diphtheriae↗
PubMed2026

Microbial membrane transporters reveal trace metal niche adaptation in distinct water masses of the Southern Ocean.

BACKGROUND: Trace metals are co-factors for enzymes that are essential for microbial metabolism and the cycling of major elements. Membrane transporters allow microbes to sense and react to trace elements in the environment and to balance their uptake and export for the regulation of intracellular metal homeostasis. The acquisition and efflux of trace metals could lead to reciprocal feedbacks between microbes and the surrounding environment. Whether these processes vary among trace metals and across habitats is presently not known. We used membrane transporters into and out of the cell as indicators for the uptake and efflux of trace metals and provide a detailed picture of the distribution of the respective genes in distinct provinces in surface waters and in subsurface water masses across a transect in the Southern Indian Ocean. RESULTS: We observed marked spatial and vertical patterns in normalized gene abundances of transporters of iron (Fe), manganese (Mn), nickel (Ni) and copper (Cu). Changes in gene abundances were specific to the type of transporter and trace metal, and pronounced differences between surface and specific water masses emerged. We found an enrichment in genes related to efflux and homeostasis of Fe, Ni and Cu in two water masses of the deep ocean that are North Atlantic Deep Water (NADW) and Lower Circumpolar Deep Water (LCDW). This pattern was observed on the community level and for metagenome-assembled genomes (MAGs) affiliated with Alteromonadaceae and Burkholderiaceae that were abundant in these two water masses. CONCLUSIONS: The enrichment in trace metal efflux and resistance genes points to microbially mediated processes, exerted by homeostasis, with potential influence on the trace metal speciation and distribution in specific water masses in the deep ocean. The gene repertoire and distinct distribution pattern of the taxa identified as potential key players could reflect an adaptation to these old water masses with trace metals acting as selective driver. Video Abstract.

Membrane Transport Proteins↗
PubMed2026

Genome-Wide Characterization of the ZIP Transporter Family in Sea Island Cotton (Gossypium barbadense L.) and Expression Profiling Under Heavy Metal and Pathogen Stresses.

G. barbadense represents an indispensable germplasm resource for high-quality textile fiber and disease resistance; nevertheless, systematic information regarding its ZRT/IRT-like protein (ZIP) gene family remains limited. Here, a total of 46 GbZIP genes were identified across the G. barbadense genome. Comprehensive bioinformatic investigations revealed uneven chromosomal distribution and confirmed that segmental/whole-genome duplications, supplemented by localized tandem duplications, drove family expansion. Members clustered within the same phylogenetic clades shared conserved motif organization and gene architecture, while promoter regions harbored abundant cis-acting elements associated with phytohormone and stress signaling. Transcriptome profiling indicated distinct expression patterns across vegetative/reproductive tissues, fiber and ovule developmental stages, and diverse abiotic stress conditions (cold, hot, drought, and salt). Quantitative Real-Time PCR (qRT-PCR) further validated that several GbZIP candidates exhibited temporal expression variations upon exposure to cadmium toxicity, V. dahliae infection, and combined Cd-V. dahliae stress. Specifically, GbZIP13, GbZIP18, GbZIP27, and GbZIP36 displayed prominent broad-spectrum responses to all three stress conditions, whereas GbZIP16, GbZIP29, and GbZIP30 showed stress-specific regulatory divergence. Overall, this study aims to systematically analyze the evolutionary characteristics and expression patterns of the GbZIP family, and to specifically evaluate the response differences under Cd stress, V. dahliae stress, and combined stress, in order to identify potential key candidate genes.

Gossypium barbadense↗
PubMed2026

Genome sequence of Staphylococcus epidermidis H1G7 from hilsa (Tenualosa ilisha) gut.

We report the genome of Staphylococcus epidermidis strain H1G7 from hilsa (Tenualosa Ilisha) fish gut. Nanopore sequencing produced a 2.5-Mb assembly (32% GC, two contigs). The genome encodes metal-chelate transport, short-chain fatty acid production, and biosynthetic clusters and lacks virulent factors, revealing genomic features potentially associated with beneficial host interactions.

cyclodipeptide synthase↗
PubMed2026

Molecular determinants associated with resistance to imipenem and imipenem-relebactam in clinical Pseudomonas aeruginosa isolates.

BACKGROUND: Pseudomonas aeruginosa accounts for 10-20% of hospital-acquired infections and is a major pathogen in immunocompromised patients. Combination therapies with beta-lactam antibiotics and beta-lactamase inhibitors, such as imipenem-relebactam have improved treatment options, yet resistant strains have already emerged, with mechanisms still not fully elucidated. RESULTS: We sequenced and analyzed 10 clinical P. aeruginosa isolates resistant to imipenem-relebactam (IMI/REL) and compared them with publicly available genomes of imipenem-resistant (IMI-R) and imipenem-susceptible (IMI-S) strains. Resistance genes were identified using the RGI CARD database, while amino acid variations in core-genome proteins were evaluated through Gene Ontology overrepresentation analysis (GO), followed by GWAS. In total, 15,758 ARGs were detected, 25.85% associated with carbapenem resistance, but only 568 classified as beta-lactamases. Among IMI/REL isolates, 36.36% carried Ambler class A and 54.54% class B beta-lactamases, contrasting with much lower frequencies in IMI-R (5.4% and 3.6%) and IMI-S (0% and 0.73%). Core-genome analysis revealed 1,106 proteins with resistance-associated variations. Comparative analyzes identified 1,618 proteins differing between IMI/REL and IMI-R genomes, and 1,015 differing between IMI/REL and all other strains. GWAS highlighted candidate genes with strong statistical associations, including those involved in metal ion transport (e.g., tonB, foxA, phuR, pfeA) and efflux pumps (e.g., czcB), as well as regulators such as mexT and biofilm-related proteins. CONCLUSIONS: These findings suggest that, beyond classical beta-lactamases, resistance may be associated with multifactorial contributions from periplasmic and outer membrane proteins, metal ion homeostasis, efflux regulation, and biofilm-associated pathways. Our results expand current knowledge of P. aeruginosa resistome and highlight novel genomic signatures potentially driving resistance to imipenem-relebactam.

Imipenem↗
PubMed2026

Common genetic mechanisms between obesity and COVID-19 severity: unravelling pleiotropic loci and biological pathways.

COVID-19 and obesity are complex conditions marked by immune and metabolic dysfunction, with the former still ranking among the leading causes of death from infectious diseases worldwide and the latter reaching pandemic proportions. Clinical evidence consistently shows that obesity increases the risk of severe COVID-19, yet the biological mechanisms underlying this association remain unclear. Given their physiological and clinical overlap, they may share genetic pathways. We investigated genetic variants jointly associated with body mass index (BMI) and COVID-19 using publicly available genome-wide data. A conjunctional false discovery rate (conjFDR) approach identified shared variants between BMI and three COVID-19 phenotypes: infection, hospitalization and very severe respiratory illness. Functional annotation and pathway enrichment analyses were performed to explore the biological context of these variants, followed by a phenome-wide association study (PheWAS) to characterize pleiotropy. Shared variants were enriched in immune, metabolic and hormonal signaling pathways, including metal ion transport and glycosylation. The overlap with BMI was strongest for hospitalized and severe cases, suggesting common mechanisms underlying disease progression rather than infection. These findings suggest a biologically meaningful genetic overlap between obesity and COVID-19 severity, highlighting pleiotropy as a key feature in complex disease interactions and potential shared therapeutic targets.

BMI↗
PubMed1978

Newer aspects of pernicious anemia.

Although readily treatable with vitamin B12, pernicious anemia continues to captivate investigative endeavors of those interested in the pathophysiology and pathogenesis of this disorder. Notable advances have been made in understanding properties of intrinsic factor, vitamin B12-binding proteins, structure and de novo synthesis of vitamin B12, mechanism of action of vitamin B12-dependent enzymes in man, and metabolic consequences of reduced activities of these enzymes in pernicious anemia. Similarly, newer morphological observations have given information regarding pathogenesis of some of the cytological abnormalities found in megaloblasts, and recent cytochemical studies have shed light on abnormalities of nuclear and cytoplasmic constituents in vitamin B12-deficient cells. Both cellular and humoral factors may contribute to immune-mediated processes in pernicious anemia, although as yet, it has not been established with certainty that pernicious anemia is an autoimmune disorder. As we look ahead, it will be important to define the process or processes responsible for atrophic gastritis, which is the pathophysiological basis of pernicious anemia. Likewise, advances in biophysics used in the study of cell membranes, cell surface phenomena, and metallic ion transport may find applicability in the study of pernicious anemia and perhaps provide further insights into metabolic abnormalities responsible for the development of megaloblastosis.

Anemia, Pernicious↗
PubMed2026

Genomic analysis of Neisseria gonorrhoeae strains from disseminated, urogenital, and rectal infections reveals differences in genes for iron acquisition and type IV secretion.

Neisseria gonorrhoeae, an obligate human pathogen, causes the sexually transmitted infection gonorrhea. Delayed treatment or immunodeficiencies can result in a higher risk of disseminated gonococcal infection (DGI), where the infection spreads to normally sterile anatomic sites, including the bloodstream. The gonococcus produces TonB-dependent transporters (TdTs) to sequester metals from host nutritional immunity proteins. These transporters are critical for survival and are important virulence factors. We characterized genes encoding iron-regulated TdTs in the genomes of strains from disseminated (n = 47), urogenital (n = 86), and rectal (n = 12) infections. We found that gonococcal strains isolated from DGI infections were more likely to express a functional hemoglobin-iron utilization operon (hpuAB wild type and phase on [32%, n = 15/47]), to harbor nonsense mutations in tdfF (57%, n = 27/47), and were predicted to express low levels of fetA (43%, n = 20/47) when compared to strains from urogenital or rectal infections. In contrast, gonococcal strains from localized urogenital infections were associated with a higher frequency of functional tdfF genes (66%, n = 57/86) and high fetA expression (30%, n = 26/86). Additionally, strains from rectal infections were more frequently found to have high fetA expression (33%, n = 4/12) and a functional tdfF (75%, n = 9/12). Furthermore, we identified associations between the presence and absence of tdfF and the gonococcal genetic island, which encodes a type IV secretion system. These findings inform our evolving understanding of the molecular mechanisms underlying disseminated gonococcal infections.IMPORTANCEGonorrhea is an emerging, global health threat, with over 100 million new cases each year. Delayed treatment, immunosuppressive medications, and immunodeficiencies can contribute to the spread of infection to the blood, presenting as a serious disseminated manifestation. With rising antimicrobial resistance and no licensed preventative vaccine, untreatable gonorrhea is a possibility in the near future. TonB-dependent transporters are highly conserved and vital for metal acquisition and survival, making them promising targets for therapeutic or preventative strategies. Associated surface-exposed lipoproteins display greater sequence variation but contribute to metal acquisition. We analyzed the genes encoding TonB-dependent transporters and associated lipoproteins from strains associated with distinct disease manifestations. We conclude that gonococci isolated from disseminated, urogenital, and rectal sites demonstrate different phase and allelic variations in genes encoding iron transport systems and the gonococcal genetic island.

Humans↗
PubMed1979

Toxic substances and cell membrane function.

The exposed location and functional importance of cell membranes make them particularly susceptible to the toxic effects of many chemicals. The likelihood of such effects has been appreciated for many years. However, the recent advent of new techniques has greatly increased our understanding of the complexities of membrane structure and function. These data make it quite clear that the interaction of toxic compounds with either the protein or the lipid component of cell membranes may substantially alter membrane function. This paper summarizes the current concepts of membrane structure and function and discusses the techniques currently in use to study cell membranes. Several examples are presented in which xenobiotics significantly alter membrane function. These include effects of heavy metals on passive ion permeability, impairment of osmoregulation and calcium transport by organochlorine pesticides, inhibition of the transport of neurotransmitter metabolites by phenoxyacetic acid herbicides in choroid plexus, and reduction in intestinal nutrient transport by heavy metals. Hence the study of the interactions of foreign compounds with membrane function may enhance our understanding of mechanisms both of toxicity and of basic membrane function.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1977

Effects of cysteine upon tumor cells.

Cysteine had been reported to increase survival time in thymoma-bearing mice and the interpretation suggested was that this was due to inhibition of a collagenase activity associated with some tumor cells by a chelating action of cysteine. In the present work it was shown that cysteine was a particularly potent inhibitor of amino acid transport into S37 ascites tumor cells, raising another possible interpretation of the earlier data. Sarcomas have previously been reported to lack collagenase activity; a survival study using S37 cells was therefore undertaken in an attempt to distinguish between possible interpretations of the earlier data involving thymomas. A null result was obtained with either cysteine or EDTA, reinforcing the earlier interpretation that survival enhancement with thymoma-bearing mice was due to an effect on collagenase. Other sulfhydryl analogs were found to inhibit transport also, and the effect was more pronounced with system L than system A. The reason for cysteine's particularly potent action on amino acid transport may be associated either with chelation of a metal ion involved in transport, or the involvement of the gamma-glutamyl cycle in the support of amino acid transport.

Amino Acids↗
PubMed1979

The distribution of metallic constituents in dentin subjected to iontophoresis.

The concentration gradient and distribution of a metallic constituent in dentin which has been subjected to iontophoresis, using a water solution of silver diamine hydroxide and zinc chloride, were analyzed by means of EPMA as a basic study for pulp capping or cavity lining. Line scanning analyses parallel to the tooth axis showed that the transportation distance of metallic ions depends strongly on potential, period of iontophoresis and structural differences in dentin. Although metallic silver or zinc was found in the dentinal tubules, there was one case in which no metal was observed. The change in the distribution can be described as power function.

Calcium↗
PubMed1977

Regulation of heme pathway enzymes and cellular glutathione content by metals that do not chelate with tetrapyrroles: blockade of metal effects by thiols.

The trace metals nickel and platinum, which are not substrates for ferrochelatase and thus do not form heme in biological systems, were found to act similaryl to cobalt, and heme itself, in regulating heme metabolism in liver and kidney. These metals induced heme oxygenase activity in both organs with the peak of induced enzyme activity reached approximately 16 hr after single injections in rats. Both metals caused transient depression of cellular glutathione content followed by increases above normal after 12 hr in liver. Nickel and platinum were more potent inducers of heme oxygenase in kidney than in liver (10-13 times normal versus 5-6 times normal). At high concentrations, they inhibited heme oxygenase [heme, hydrogen-donor:oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating), EC 1.14.99.3] in vitro. Both were active in regulating heme metabolism only when administered in the ionic form. Complexing of the metals with sulfhydryl agents completely blocked their actions on heme metabolism. Administration of cysteine orally prior to or shortly after administration of the metals had a similar blocking effect. Nickel and platinum produced depression of delta-aminolevulinate synthase [succinyl-CoA:glycine c-succinyltransferase (decarboxylating), EC 2.3.1.37] activity in liver, but neigther inhibited this rate-limiting ennzyme for heme synthesis in vitro. Furthermore, despite the substantial decreases in cellular heme and hemoprotein contents mediated by the metal, production of delta-amimolevulinate synthase did not undergo the compensatory increase that would be expected if there were a direct reciprocal feedback relationship between cellular heme level and synthesis of this enzyme. These findings indicate that it is not necessary for metal ions to be chelated in the porphyrin ring in order to regulate the enzymes of heme synthesis and heme oxidation. Accordingly, it is suggested that the iron atom of heme is the proximately active regulator of delta-aminolevulinate synthase and heme oxygenase--actions generally ascribed to the iron-tetrapyrrole complex itself--and that the tetrapyrrole moiety of the complex functions primarily as a means of transport of the metal to regulatory sites in cells.

5-Aminolevulinate Synthetase↗