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PubMed1990

Role of zinc in regulating the testicular function. Part 3. Histopathological changes induced by dietary zinc deficiency in testes of male albino rats.

Zinc deficiency affects the testicular tissues adversely. The testes of zinc-deficient rats showed variable degrees of degeneration compared to both control and zinc-supplemented ones. Initially, there was an early pronounced spermatic arrest followed by a series of degeneration of the cellular layers constituting the seminiferous tubules in the zinc-deficient rats. Degenerative changes were additionally demonstrated in the interstitial tissue cells of the zinc-deficient rats. These histopathological observations in testes of zinc-deficient rats run in parallel provide an additional support to our previous publications in which we recorded a significant reduction in both serum and testicular levels of testosterone in the same group of animals, since spermatogenesis in rodents appeared to depend primarily on testosterone level.

Animals↗

PubMed2001

Hydrogen peroxide damages the zinc-binding site of zinc-deficient Cu,Zn superoxide dismutase.

Mutations in Cu,Zn superoxide dismutase (Cu,Zn SOD) account for approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS), a late-onset neurodegenerative disease affecting motor neurons. These mutations decrease protein stability and lower zinc affinity. Zinc-deficient SOD (Cu,E SOD) has altered redox activities and is toxic to motor neurons in vitro. Using bovine SOD, we studied the effects of hydrogen peroxide (H(2)O(2)) on Cu,E SOD and Cu,Zn SOD. Hydrogen peroxide treatment of Cu,E SOD inactivated zinc binding activity six times faster than superoxide dismutase activity, whereas inactivation of dismutase activity occurred at the same rate for both Cu,Zn SOD and Cu,E SOD. Zinc binding by Cu,E SOD was also damaged by simultaneous generation of superoxide and hydrogen peroxide by xanthine oxidase plus xanthine. Although urate, xanthine, and ascorbate can protect superoxide dismutase activity of Cu,Zn SOD from inactivation, they were not effective at protecting Cu,E SOD. Hydrogen peroxide induced subtle changes in the tertiary structure but not the secondary structure of Cu,E SOD as detected by near and far UV circular dichroism. Our results suggest that low levels of hydrogen peroxide could potentially enhance the toxicity of zinc deficient SOD to motor neurons in ALS by rendering zinc loss from SOD irreversible.

Amyotrophic Lateral Sclerosis↗

PubMed2000

Expression of ZRC1 coding for suppressor of zinc toxicity is induced by zinc-starvation stress in Zap1-dependent fashion in Saccharomyces cerevisiae.

The ZRC1 gene was cloned as a multicopy suppressor of zinc toxicity in Saccharomyces cerevisiae. Zrc1 belongs to CDF (cation diffusion facilitator) family. The transporters belonging to this family are thought to play an important role in metal detoxification. However, we found that cell growth of zrc1Delta mutant was lowered under the metal-limited conditions, which was restored by zinc. The Zap1 transcription factor is crucial for expression of several genes responsive to zinc-starvation stress. The expression of ZRC1 was induced in Zap1-dependent fashion when the intracellular zinc level was decreased and this induction was repressed by zinc. These results imply an important role of Zrc1 in the zinc-starvation stress.

Base Sequence↗

PubMed2001

Changes in zinc ligation promote remodeling of the active site in the zinc hydrolase superfamily.

The zinc hydrolase superfamily is a group of divergently related proteins that are predominantly enzymes with a zinc-based catalytic mechanism. The common structural scaffold of the superfamily consists of an eight-stranded beta-sheet flanked by six alpha-helices. Previous analyses, while acknowledging the likely divergent origins of leucine aminopeptidase, carboxypeptidase A and the co-catalytic enzymes of the metallopeptidase H clan based on their structural scaffolds, have failed to find any homology between the active sites in leucine aminopeptidase and the metallopeptidase H clan enzymes. Here we show that these two groups of co-catalytic enzymes have overlapping dizinc centers where one of the two zinc atoms is conserved in each group. Carboxypeptidase A and leucine aminopeptidase, on the other hand, no longer share any homologous zinc-binding sites. At least three catalytic zinc-binding sites have existed in the structural scaffold over the period of history defined by available structures. Comparison of enzyme-inhibitor complexes show that major remodeling of the substrate-binding site has occurred in association with each change in zinc ligation in the binding site. These changes involve re-registration and re-orientation of the substrate. Some residues important to the catalytic mechanism are not conserved amongst members. We discuss how molecules acting in trans may have facilitated the mutation of catalytically important residues in the active site in this group.

Amino Acid Sequence↗

PubMed1992

Blood zinc status and zinc treatment in human immunodeficiency virus-infected patients.

We investigated the zinc concentration in blood and the effect of zinc supplementation in 11 male outpatients seropositive for human immunodeficiency virus at stage 5 according to the Walter Reed classification. Zinc concentration was measured in serum, platelets, mononuclear and polymorphonuclear cells, and erythrocytes. There was a significant increase in serum zinc concentration after zinc administration, but the zinc level in blood cells remained unchanged. All patients showed a progressive gain in body weight and a slight elevation in levels of CD4+ cells. No adverse side-effects were noticed.

Adolescent↗

PubMed1983

Zinc levels in zinc-stabilized insulin are inhibitory to the growth of cells in vitro.

Adult human prostatic epithelium was cultured in a defined medium consisting of RPMI 1640 supplemented with transferrin, insulin, epidermal growth factor, dexamethasone, and vitamin A. In the presence of insulin, stabilized with zinc, maximum epithelial multiplication was obtained at an insulin concentration of 0.03 to 0.1 U/ml, corresponding to a zinc concentration of 1.4 X 10(-7) M. At higher insulin concentrations, growth stimulation declined. Zinc-free insulin, on the other hand, stimulated cell multiplication with an optimum concentration of 0.3 to 1.0 U/ml. At this concentration, the maximum growth was twice that obtained with zinc-stabilized insulin. Results demonstrate that growth inhibition caused by zinc limits the concentration of zinc-stabilized insulin, which can be used in serum-free, defined culture media.

Aged↗

PubMed1991

Parenteral supplementation with zinc in surgical patients corrects postoperative serum-zinc drop.

Zinc has been known for a long time to facilitate wound healing. But, so far, supplementation trials in patients treated by major severity surgery gave either partial or controversial results. In a double-blind, randomized study including 30 patients, we show that zinc supplements (30 mg/d for 3 d) administered by a drip correct postoperative drop of serum zinc, that this correction concerns the available part of serum zinc (i.e., zinc that is bound to compounds other than alpha-2 macroglobulin in serum), and that this supplementation can improve clinical wound healing. Possible influence of increased urinary output after the intervention is discussed, and we found that serum cortisol remains stable when zinc/albumin ratio is stable, and increases sharply when the same ratio drops. Cortisol, therefore, seems to play a major role in zinc redistribution after surgery.

Aorta, Abdominal↗

PubMed1982

Studies on the serum levels of iron, copper and zinc and the urinary excretion of zinc after burn injury.

The levels of iron, copper and zinc in the serum of patients suffering burn injuries were measured. It was observed that serum zinc and copper did not change significantly after burn injury; values lying outside the laboratory's own normal range were rarely observed. There was a considerable increase in the output of zinc in the urine after burn injury. Raised levels of zinc in the urine were not observed until about a week after injury, but after that time highly significant changes occurred. The considerable day-to-day variation in zinc output suggests that a variety of causes give rise to the increased zinc excretion.

Adolescent↗

PubMed2004

Interference of magnesium on zinc adsorption by pond sediment and on zinc accumulation in a freshwater teleost, Labeo rohita (Hamilton).

Two experiments were conducted to evaluate the interference of magnesium on zinc adsorption in freshwater fish pond sediment and zinc accumulation in the freshwater teleost Labeo rohita (Hamilton). The study demonstrated that increasing the concentration of magnesium as magnesium sulfate from 100 to 400 mg kg(-1) decreased the adsorption of zinc in sediment. The maximum adsorption was found at a concentration of 100 mg kg(-1) of Mg(2+) and the minimum with 400 mg kg(-1) of Mg(2+). This study also demonstrated that the exposure of fish to 0.25 mg L(-1) of zinc as zinc sulfate with different concentrations of magnesium (100, 200, 300, and 400 mg L(-1)) for 14 d resulted in the minimum accumulation of zinc in L. rohita (2.97 mg kg(-1) dry weight) at 200 mg L(-1) of Mg(2+), while the maximum accumulation (8.47 mg kg(-1) dry weight) occurred with no magnesium treatment.

Animals↗

PubMed2005

Reactivity of zinc finger cysteines: chemical modifications within labile zinc fingers in estrogen receptor.

Estrogen receptor (ER, alpha isoform) is a 67 kDa zinc finger transcription factor that plays a fundamental role in both normal reproductive gland development and breast carcinogenesis, and also represents a critical molecular target for breast cancer therapy. We are investigating the structural consequences of chemical exposures thought to modify essential zinc finger cysteine residues in human ER. The current study employs mass spectrometry to probe ER zinc finger structural changes induced by a redox-reactive vitamin K3 analog, menadione; a commonly used cysteine alkylator, iodoacetic acid; and a thiol alkylating fluorophore, monobromobimane. Although they are slower to react, the sterically bulkier reagents, monobromobimane and menadione, effectively alkylate the most susceptible ER zinc finger cysteine sulfhydryl groups. Menadione arylation results first in Michael addition of the hydroquinone followed by rapid oxidation to the corresponding quinone, evidenced by a 2 Da mass loss per cysteine residue. Mass spectrometric analysis performed under MALDI conditions reveals both hydroquinone and quinone forms of arylated menadione, whereas only the quinone product is detectable under ESI conditions. Tandem mass spectrometry of a synthetic peptide encompassing the C-terminal half of the structurally more labile second zinc finger of ER (ZnF2B) demonstrates that the two nucleophilic thiols in ZnF2B (Cys-237, Cys-240) are not chemically equivalent in their reactivity to bromobimane or menadione, consistent with their unequal positioning near basic amino acids that affect thiol pKa, thereby rendering Cys-240 more reactive than Cys-237. These findings demonstrate important differential susceptibility of ER zinc finger cysteine residues to thiol reactions.

Binding Sites↗

PubMed1983

Serum zinc, copper, retinol-binding protein, prealbumin, and ceruloplasmin concentrations in infants receiving intravenous zinc and copper supplementation.

One hundred twenty-seven newborn infants requiring parenteral nutrition were randomly assigned to receive differing amounts of zinc (40 to 400 micrograms/kg/day) and copper (20 or 40 micrograms/kg/day) supplementation within five birth weight groups (600 to 2,500 gm). The serum zinc concentration remained relatively constant in the group receiving the most zinc supplementation after two weeks of therapy, but declined sharply in the groups receiving less supplementation. No effect of increased copper intake was noted on ceruloplasmin values, but a difference in serum copper concentrations was noted at two weeks. No correlation was noted between serum zinc and copper values or among those for serum zinc, retinol-binding protein, and prealbumin. Reference ranges were defined for serum zinc, copper, retinol-binding protein, prealbumin, and ceruloplasmin in the preterm infant.

Birth Weight↗

PubMed2001

Zinc acclimation and its effect on the zinc tolerance of Raphidocelis subcapitata and Chlorella vulgaris in laboratory experiments.

The effect of zinc acclimation of Raphidocelis subcapitata (syn. Selenastrum capricornutum) and Chlorella vulgaris on their sensitivity towards this metal was examined in a series of laboratory experiments. These two commonly used algal species were acclimated to 65 microg Zn/l and changes in zinc tolerance were monitored using standard growth inhibition tests. The chemically defined ISO medium was used as a control culture medium. Both species demonstrated a maximum increase in zinc tolerance of a factor of 3 after 100 days of acclimation. Shifts in the shape of the concentration-response curve due to acclimation were observed for R. subcapitata. Compared to non-acclimated algae, acclimated R. subcapitata exhibited higher growth rates in all zinc treatments as well as in the controls. This suggests that the use of ISO-medium results in sub-optimal growth due to zinc deficiency. These effects could not be demonstrated for C. vulgaris. The zinc tolerance of both species decreased significantly one week after returning the acclimated algae to control (ISO) medium. 72hEC50 values based on growth rate were two to four times higher than those calculated using biomass measurements. Algal toxicity test results, particularly if used for metal risk assessments, must not be conducted using nutrient deficient media.

Acclimatization↗

PubMed2001

Multiconnection of identical zinc finger: implication for DNA binding affinity and unit modulation of the three zinc finger domain.

Cys(2)-His(2)-type zinc finger proteins have a tandemly repeated array structure consisting of independent finger modules. They are expected to elevate the DNA binding affinity and specificity by increasing the number of finger modules. To investigate the relation between the number and the DNA binding affinity of the zinc finger, we have designed the two- to four-finger peptides by connecting the central zinc finger (finger 2) of Sp1 with the canonical linker sequence, Thr-Gly-Glu-Lys-Pro. Gel mobility shift assays reveal that the cognate three- and four-finger peptides, Sp1(zf222) and Sp1(zf2222), strongly bind to the predicted target sequences, but the two-finger peptide, Sp1(zf22), does not. Of special interest is the fact that the dissociation constant for Sp1(zf2222) binding to the target DNA is comparable to that for Sp1(zf222). The methylation interference, DNase I and hydroxyl radical footprintings, and circular permutation analyses demonstrate that Sp1(zf2222) binds to its target site with three successive zinc fingers and the binding of the fourth zinc finger is inhibited by DNA bending induced by the binding of the three-finger domain. The present results strongly indicate that the zinc finger protein binds to DNA by the three-finger domain as one binding unit. In addition, this information provides the basis for the design of a novel multifinger protein with high affinity and specificity for long DNA sequences, such as chromosomal DNAs.

Base Sequence↗

PubMed1993

The crystal structure of a two zinc-finger peptide reveals an extension to the rules for zinc-finger/DNA recognition.

The Cys2-His2 zinc-finger is the most widely occurring DNA-binding motif. The first structure of a zinc-finger/DNA complex revealed a fairly simple mechanism for DNA recognition suggesting that the zinc-finger might represent a candidate template for designing proteins to recognize DNA. Residues at three key positions in an alpha-helical 'reading head' play a dominant role in base-recognition and have been targets for mutagenesis experiments aimed at deriving a recognition code. Here we report the structure of a two zinc-finger DNA-binding domain from the protein Tramtrack complexed with DNA. The amino-terminal zinc-finger and its interaction with DNA illustrate several novel features. These include the use of a serine residue, which is semi-conserved and located outside the three key positions, to make a base contact. Its role in base-recognition correlates with a large, local, protein-induced deformation of the DNA helix at a flexible A-T-A sequence and may give insight into previous mutagenesis experiments. It is apparent from this structure that zinc-finger/DNA recognition is more complex than was originally perceived.

Amino Acid Sequence↗

PubMed2005

Zinc- and iron-dependent cytosolic metallo-beta-lactamase domain proteins exhibit similar zinc-binding affinities, independent of an atypical glutamate at the metal-binding site.

ZiPD (zinc phosphodiesterase; synonyms are ElaC, ecoZ, RNaseZ and 3' tRNase) and the iron-dependent redox enzyme FlRd (flavorubredoxin) from Escherichia coli represent prototypical cases of proteins sharing the metallo-beta-lactamase fold that require strict metal selectivity for catalytic activity, yet their metal selectivity has only been partially understood. In contrast with hydrolytic metallo-beta-lactamase proteins, iron-dependent FlRd-like enzymes have an atypical glutamate ligand, which replaces one otherwise conserved histidine ligand. X-ray absorption spectroscopy revealed that the FlRd metallo-beta-lactamase domain is capable of incorporating two zinc ions into the binuclear metal-binding site. Zinc dissociation constants, determined by isothermal titration calorimetry are similar for zinc binding to E. coli ZiPD (K(d1)=2.2+/-0.2 microM and K(d2)=23.0+/-0.6 microM) and to the E. coli FlRd metallo-beta-lactamase domain (K(d1)=0.7+/-0.1 microM and K(d2)=26.0+/-0.1 microM). In good correspondence, apo-ZiPD requires incubation with 10 microM zinc for full reconstitution of the phosphodiesterase activity. Accordingly, metal selectivity of ZiPD and FlRd only partially relies on first shell metal ligands. Back mutation of the atypical glutamate in FlRd to a histidine unexpectedly resulted in an increased first zinc dissociation constant (K(d1)=30+/-4 microM and K(d2)=23+/-2 microM). In combination with a recent mutational study on ZiPD [Vogel, Schilling and Meyer-Klaucke (2004) Biochemistry 43, 10379-10386], we conclude that the atypical glutamate does not guide metal selectivity of the FlRd metallo-beta-lactamase domain but suppresses possible hydrolytic cross-activity.

Apoenzymes↗

PubMed1998

Alteration of zif268 zinc-finger motifs gives rise to non-native zinc-co-ordination sites but preserves wild-type DNA recognition.

Zinc fingers are among the major structural motifs found in proteins that are involved in eukaryotic gene regulation. Many of these zinc-finger domains are involved in DNA binding. This study investigated whether the zinc-co-ordinating (Cys)2(His)2 motif found in the three zinc fingers of zif268 could be replaced by a (Cys)4 motif while still preserving DNA recognition. (Cys)2(His)2-to-(Cys)4 mutations were generated in each of the three zinc fingers of zif268 individually, as well as in fingers 1 and 3, and fingers 2 and 3 together. Whereas finger 1 and finger 3 tolerate the switch, such an alteration in finger 2 renders the polypeptide incapable of DNA recognition. The protein-DNA interaction was examined in greater detail by using a methylation-interference assay. The mutant polypeptides containing the (Cys)4 motif in fingers 1 or 3 recognize DNA in a manner identical to the wild-type protein, suggesting that the (Cys)4 motif appears to give rise to a properly folded finger. Additional results indicate that a zif268 variant containing a (Cys)2(His)(Ala) arrangement in finger 1 is also capable of DNA recognition in a manner identical to the wild-type polypeptide. This appears to be the first time that such alterations, in the context of an intact DNA-binding domain, have still allowed for specific DNA recognition. Taken together, the work presented here enhances our understanding of the relationship between metal ligation and DNA-binding by zinc fingers.

Amino Acid Sequence↗

PubMed1996

Mutations in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein.

A series of mutant human and yeast copper-zinc superoxide dismutases has been prepared, with mutations corresponding to those found in familial amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease). These proteins have been characterized with respect to their metal-binding characteristics and their redox reactivities. Replacement of Zn2+ ion in the zinc sites of several of these proteins with either Cu2+ or Co2+ gave metal-substituted derivatives with spectroscopic properties different from those of the analogous derivative of the wild-type proteins, indicating that the geometries of binding of these metal ions to the zinc site were affected by the mutations. Several of the ALS-associated mutant copper-zinc superoxide dismutases were also found to be reduced by ascorbate at significantly greater rate than the wild-type proteins. We conclude that similar alterations in the properties of the zinc binding site can be caused by mutations scattered throughout the protein structure. This finding may help to explain what is perhaps the most perplexing question in copper-zinc superoxide dismutase-associated familial ALS-i.e., how such a diverse set of mutations can result in the same gain of function that causes the disease.

Amyotrophic Lateral Sclerosis↗

PubMed1999

Metallothionein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation.

Metallothionein (MT) is a small cysteine-rich protein thought to play a critical role in cellular detoxification of inorganic species by sequestering metal ions that are present in elevated concentrations. We demonstrate here that metallothionein can play an important role at the other end of the homeostatic spectrum by scavenging an essential metal in a mouse fibroblast cell line that has been cultured under conditions of extreme zinc deprivation (LZA-LTK-). These cells unexpectedly produce constitutively high levels of metallothionein mRNA; however, the MT protein accumulates only when high concentrations of zinc are provided in the media. Until this MT pool is saturated, no measurable zinc remains in the external media. In this case, zinc deprivation leads to amplification of the MT gene locus in the LZA-LTK- cell line. Furthermore, the intracellular zinc levels in the fully adapted cells remain at the normal level of 0.4 fmol zinc/cell, even when extracellular zinc concentration is decreased by 2 orders of magnitude relative to normal media.

3T3 Cells↗