Zinc Protoporphyrin IX Binds Heme Crystals to Inhibit the Process of Crystallization in Plasmodium falciparum

Iyer, Jayasree K.; Shi, Lirong; Shankar, Anuraj H.; Sullivan, David J.

doi:10.1007/bf03402182

Cited by 31 publications

(24 citation statements)

References 39 publications

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“…Various compounds have been used to inhibit CO synthesis derived from HO in animals and plants. The potent HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) was first found to inhibit HO activity in both animals and plants (Lamar et al, 1996;Iyer et al, 2003;Lang et al, 2005;Liu et al, 2007;Xuan et al, 2007;Song et al, 2008). In our test, treating auxin-depleted cucumber explants with this compound prevents the induction action of IAA or hematin on adventitious root formation (Fig.…”

Section: The Application Of Zinc Protoporphyrin IX To Auxin-depleted mentioning

confidence: 79%

The Heme Oxygenase/Carbon Monoxide System Is Involved in the Auxin-Induced Cucumber Adventitious Rooting Process

et al. 2008

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Indole acetic acid (IAA) is an important regulator of adventitious rooting via the activation of complex signaling cascades. In animals, carbon monoxide (CO), mainly generated by heme oxygenases (HOs), is a significant modulator of inflammatory reactions, affecting cell proliferation and the production of growth factors. In this report, we show that treatment with the auxin transport inhibitor naphthylphthalamic acid prevented auxin-mediated induction of adventitious rooting and also decreased the activity of HO and its by-product CO content. The application of IAA, HO-1 activator/CO donor hematin, or CO aqueous solution was able to alleviate the IAA depletion-induced inhibition of adventitious root formation. Meanwhile, IAA or hematin treatment rapidly activated HO activity or HO-1 protein expression, and CO content was also enhanced. The application of the HO-1-specific inhibitor zinc protoporphyrin IX (ZnPPIX) could inhibit the above IAA and hematin responses. CO aqueous solution treatment was able to ameliorate the ZnPPIX-induced inhibition of adventitious rooting. Molecular evidence further showed that ZnPPIX mimicked the effects of naphthylphthalamic acid on the inhibition of adventitious rooting, the down-regulation of one DnaJ-like gene (CSDNAJ-1), and two calcium-dependent protein kinase genes (CSCDPK1 and CSCDPK5). Application of CO aqueous solution not only dose-dependently blocked IAA depletion-induced inhibition of adventitious rooting but also enhanced endogenous CO content and up-regulated CSDNAJ-1 and CSCDPK1/5 transcripts. Together, we provided pharmacological, physiological, and molecular evidence that auxin rapidly activates HO activity and that the product of HO action, CO, then triggers the signal transduction events that lead to the auxin responses of adventitious root formation in cucumber (Cucumis sativus).

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Section: The Application Of Zinc Protoporphyrin IX To Auxin-depleted mentioning

confidence: 79%

The Heme Oxygenase/Carbon Monoxide System Is Involved in the Auxin-Induced Cucumber Adventitious Rooting Process

et al. 2008

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“…ZnPP is an endogenous metalloporphyrin formed under various clinical conditions (28,34). The role of ZnPP in inhibiting tumor progression has been ascribed to its ability to inhibit HO activity (3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Fernando

Wang

et al. 2009

Journal of Biological Chemistry

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Zinc protoporphyrin IX (ZnPP), an endogenous heme analogue that inhibits heme oxygenase (HO) activity, represses tumor growth. It can also translocate into the nucleus and upregulate heme oxygenase 1 (HMOX1) gene expression. Here, we demonstrate that tumor cell proliferation was inhibited by ZnPP, whereas tin protoporphyrin (SnPP), another equally potent HO-1 inhibitor, had no effect. Microarray analysis on 128 tumorigenesis related genes showed that ZnPP suppressed genes involved in cell proliferation and angiogenesis. Among these genes, CYCLIN D1 (CCND1) was specifically inhibited as were its mRNA and protein levels. Additionally, ZnPP inhibited CCND1 promoter activity through an Sp1 and Egr1 overlapping binding site (S/E). We confirmed that ZnPP modulated the S/E site, at least partially by associating with Sp1 and Egr1 proteins rather than direct binding to DNA targets. Furthermore, administration of ZnPP significantly inhibited cyclin D1 expression and progression of a B-cell leukemia/lymphoma 1 tumor in mice by preferentially targeting tumor cells. These observations show HO independent effects of ZnPP on cyclin D1 expression and tumorigenesis. Zinc protoporphyrin IX (ZnPP)2 is a metabolite formed in trace amounts during heme biosynthesis. In this process, the final reaction is the chelation of zinc in the protoporphyrin ring, whereas heme is formed by chelation of iron in the ring. During periods of iron insufficiency or impaired iron utilization, ZnPP formation is enhanced. Clinically, ZnPP quantification is a sensitive and specific tool for measuring iron mineral status and metabolism (1). In addition, ZnPP regulates heme catabolism through competitively inhibiting the activity of heme oxygenase (HO), the rate-limiting enzyme in the heme degradation pathway that produces carbon monoxide and biliverdin. The latter is rapidly reduced to bilirubin by biliverdin reductase. Thus, ZnPP has potential therapeutic applications in controlling exaggerated bilirubin formation leading to neonatal jaundice (2). Moreover, because the by-products of the HO reaction, carbon monoxide and bilirubin, are antioxidants, the potential effects of ZnPP have been studied in numerous diseases, including cancer, such as chronic myelogenous leukemia (3-6).Whereas ZnPP has been largely studied in relation to its inhibition of HO activity, reports show that ZnPP could exert cellular effects independent of HO activity (7,8). In kinetic assays, ZnPP inhibited the soluble guanylyl cyclase activity independent of HO-1 (9). In vitro studies showed that ZnPP directly interacts with human immunodeficiency virus type 1 reverse transcriptase and modulates its activity (10). We showed that ZnPP induces the expression of HMOX1 and TP53 genes and localizes to the nucleus (11). Although the underling mechanism is unknown, zinc mesoporphyrin, another analogue of heme, has been shown to induce HMOX1 expression by accelerating Bach1 protein degradation (12). Heme itself can affect gene expression by associating with transcription factors (13,14). Th...

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“…Several known antimalarials, including the known heme crystallization inhibitors AMQ and quinacrine, were among the compounds that were screening positives in the CFHCS. Additionally, several porphyrins were identified as heme crystallization inhibitors, an activity that has previously been reported for this class of compounds (3,12,15). In silico counterscreen for P. falciparum growth inhibition.…”

Section: Vol 53 2009mentioning

confidence: 69%

Colorimetric High-Throughput Screen for Detection of Heme Crystallization Inhibitors

Rush

Baniecki

Mazitschek

et al. 2009

Antimicrob Agents Chemother

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Malaria infects 500 million people annually, a number that is likely to rise as drug resistance to currently used antimalarials increases. During its intraerythrocytic stage, the causative parasite, Plasmodium falciparum, metabolizes hemoglobin and releases toxic heme, which is neutralized by a parasite-specific crystallization mechanism to form hemozoin. Evidence suggests that chloroquine, the most successful antimalarial agent in history, acts by disrupting the formation of hemozoin. Here we describe the development of a 384-well microtiter plate screen to detect small molecules that can also disrupt heme crystallization. This assay, which is based on a colorimetric assay developed by Ncokazi and Egan (K. K. Ncokazi and T. J. Egan, Anal. Biochem. 338:306-319, 2005), requires no parasites or parasite-derived reagents and no radioactive materials and is suitable for a high-throughput screening platform. The assay's reproducibility and large dynamic range are reflected by a Z factor of 0.74. A pilot screen of 16,000 small molecules belonging to diverse structural classes was conducted. The results of the target-based assay were compared with a whole-parasite viability assay of the same small molecules to identify small molecules active in both assays.

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Zinc Protoporphyrin IX Binds Heme Crystals to Inhibit the Process of Crystallization in Plasmodium falciparum

Cited by 31 publications

References 39 publications

The Heme Oxygenase/Carbon Monoxide System Is Involved in the Auxin-Induced Cucumber Adventitious Rooting Process

The Heme Oxygenase/Carbon Monoxide System Is Involved in the Auxin-Induced Cucumber Adventitious Rooting Process

Zinc Protoporphyrin Regulates Cyclin D1 Expression Independent of Heme Oxygenase Inhibition

Colorimetric High-Throughput Screen for Detection of Heme Crystallization Inhibitors

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