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Regulation of Heme Biosynthesis

N2 - The assembly and activity of cytochrome c oxidase is dependent on the availability of heme A, one of its essential cofactors. In eukaryotes, two inner mitochondrial membrane proteins, heme O synthase (Cox10) and heme A synthase (Cox15), are required for heme A biosynthesis. In this report, we demonstrate that in Saccharomyces cerevisiae the transcription of COX15 is regulated by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. Conversely, COX10, the physiological partner of COX15, does not share the same regulatory mechanism with COX15. Interestingly, protein quantification identified an 8:1 protein ratio between Cox15 and Cox10. Together, these results suggest that heme A synthase and/or heme O synthase might play a new, unidentified role in addition to heme A biosynthesis.

Regulation of Heme Biosynthesis in Salmonella …

Despite these recent advances, the detailed regulatory mechanism of heme A biosynthesis is still far from clear. Large scale genetic, molecular, and physiological approaches seem to suggest that O2 concentrations, fermentable versus non-fermentable carbon sources, rich versus minimal medium, and respiratory competence have no dramatic effect on the transcription of either HOS or HAS (–). Although these results might initially seem surprising because of the key role that heme A plays in respiration, the fact that no significant signals were detected in the large scale screening is perhaps to be expected given the low mRNA levels of COX10 and COX15. Therefore, individual analysis is required to determine the regulation of these two genes.

179, 1997 REGULATION OF HEME BIOSYNTHESIS IN S

In the yeast S. cerevisiae, CcO is composed of 11 subunits, which are mainly regulated by ATP concentration, oxygen availability, intracellular heme levels, carbon sources, and retrograde regulation (, ). In addition to the structural subunits, more than two dozen accessory proteins are required for CcO assembly and function, and their regulatory mechanism remains largely unknown (). Among these accessory proteins are HOS and HAS, which are required for the biosynthesis of the heme A cofactor.

Our previous data support a model whereby bacterial HOS and HAS interact to form a complex in which heme O is channeled directly from HOS to HAS (). Because either the conversion of heme O to heme A or the release of the heme A product appears to be rate-limiting, we hypothesize that in bacteria this HAS-HOS complex might partially regulate the flux of hemes through the heme A biosynthetic pathway. Our hypothesis is consistent with the studies of Barros and Tzagoloff in Saccharomyces cerevisiae suggesting that the activity of HOS is down-regulated either by HAS or the product of HAS (). They also hypothesized that the activity of HAS is positively regulated by a downstream CcO assembly intermediate or subunit of CcO, because most cox mutants have significantly decreased levels of heme A ().

Regulation of heme biosynthesis in Neurspora crassa.

The assembly and activity of cytochrome c oxidase is dependent on the availability of heme A, one of its essential cofactors. In eukaryotes, two inner mitochondrial membrane proteins, heme O synthase (Cox10) and heme A synthase (Cox15), are required for heme A biosynthesis. In this report, we demonstrate that in Saccharomyces cerevisiae the transcription of COX15 is regulated by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. Conversely, COX10, the physiological partner of COX15, does not share the same regulatory mechanism with COX15. Interestingly, protein quantification identified an 8:1 protein ratio between Cox15 and Cox10. Together, these results suggest that heme A synthase and/or heme O synthase might play a new, unidentified role in addition to heme A biosynthesis.

Our RT real-time PCR data revealed that the mRNA level of COX10 is approximately ten times less than that of COX15, and protein quantification confirmed that the ratio of the mRNA is reflected in the ratio of the two proteins. Previously it was generally believed that the transcription and translation of HOS and HAS are coordinated to obtain a 1:1 stoichiometry, because these two enzymes work cooperatively to synthesize heme A, and a HAS-HOS complex in bacteria is supported by our previous studies (). There are three possible explanations concerning the 8:1 stoichiometry between HAS and HOS protein levels. 1) The first possibility is that the turnover number of HAS is much lower than that of HOS, and therefore more HAS is required to synthesize enough heme A for CcO. 2) The second possibility is that HAS is in excess, and that HOS is limiting in the heme A biosynthetic pathway. This possibility is perhaps supported by the fact that co-overexpression of Mss51 and Cox10 increases both Cox1 and heme A levels in shy1Δ cells (). (If Cox10 is limiting, however, why does the majority of the regulation appear to be at Cox15?) Finally, 3) Cox15 and/or Cox10 may have dual, non-overlapping functions involving both heme A biosynthesis and some other unknown function. Recently, Shy1 and Cox14, two other CcO accessory proteins, were determined to promote the assembly of CcO with cytochrome bc1 to form a respiratory chain supercomplex (). In addition, human Sco1 and Sco2 () and Cox11 () were reported to have multiple functions in addition to aiding in the maturation of the CuA and CuB sites of CcO, respectively. Further studies are underway to ascertain whether HAS and/or HOS have a secondary function.

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  • Regulation of heme biosynthesis and transport in …

    (1993), Regulation of heme biosynthesis: Distinct regulatory features in erythroid cells

  • Regulation of the Heme A Biosynthetic Pathway - …

    Regulation of the heme a biosynthetic pathway Differential regulation of heme a synthase and heme O synthase ..

  • Regulation of Heme Biosynthesis in Escherichia coli

    Regulation of heme biosynthesis in Salmonella …

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07/01/2018 · Request (PDF) | The regulation of he..

The assembly and activity of cytochrome c oxidase is dependent on the availability of heme A, one of its essential cofactors. In eukaryotes, two inner mitochondrial membrane proteins, heme O synthase (Cox10) and heme A synthase (Cox15), are required for heme A biosynthesis. In this report, we demonstrate that in Saccharomyces cerevisiae the transcription of COX15 is regulated by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. Conversely, COX10, the physiological partner of COX15, does not share the same regulatory mechanism with COX15. Interestingly, protein quantification identified an 8:1 protein ratio between Cox15 and Cox10. Together, these results suggest that heme A synthase and/or heme O synthase might play a new, unidentified role in addition to heme A biosynthesis.

Porphyrin and Heme Synthesis and Bilirubin Metabolism

AB - The assembly and activity of cytochrome c oxidase is dependent on the availability of heme A, one of its essential cofactors. In eukaryotes, two inner mitochondrial membrane proteins, heme O synthase (Cox10) and heme A synthase (Cox15), are required for heme A biosynthesis. In this report, we demonstrate that in Saccharomyces cerevisiae the transcription of COX15 is regulated by Hap1, a transcription factor whose activity is positively controlled by intracellular heme concentration. Conversely, COX10, the physiological partner of COX15, does not share the same regulatory mechanism with COX15. Interestingly, protein quantification identified an 8:1 protein ratio between Cox15 and Cox10. Together, these results suggest that heme A synthase and/or heme O synthase might play a new, unidentified role in addition to heme A biosynthesis.

RESULTS Graphic illustration of heme regulation

Handschin C, Lin J, Rhee J, et al. (2005) Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC‐1alpha. Cell 122 (4): 505–515.

01/01/1996 · How to Cite

Quantifying the protein levels of Cox15 and Cox10 in the mss51Δ strain and the wild-type strain demonstrates that the steady-state levels of Cox15 and Cox10 are not down-regulated by the absence of Cox1, a Cox1-associated subassembly complex, or respiratory deficiency. This is contrary to the structural subunits of CcO, which are generally degraded by mitochondrial proteolysis if the respiratory chain is not competent. Our observation, coupled to the results reported by Barros and Tzagoloff (), suggest that the decreased amount of heme A observed in the absence of subunit I could be partially caused by a decrease in the turnover number of the heme A biosynthetic pathway. One logical possibility is that heme A release from HAS is a target for regulation, and that this release is facilitated either by Cox1 or by some subassembly intermediate of CcO. The downstream regulation mechanism prevents uncontrolled release of heme A and blocks the accumulation of unassociated heme A in the mitochondrion, thus avoiding potential deleterious damage to DNA and membranes. A second possibility is that either HAS or a mitochondrial ferredoxin, a potential electron donor for HAS in yeast (), can sense the mitochondrial redox potential (which is dependent on the efficiency of the respiratory chain), and that electron flow through HAS (and therefore the activity of HAS) is inhibited by respiratory deficiency. Currently we cannot distinguish between these two different possibilities.

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