Browsing by Author "Strauss, Erick"

Now showing 1 - 6 of 6
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    Complex stability and dynamic subunit interchange modulates the disparate activities of the yeast moonlighting proteins Hal3 and Vhs3
    (Springer Nature, 2015-10) Abrie, J. Albert; Molero, Cristina; Arino, Joaquin; Strauss, Erick
    Saccharomyces cerevisiae Hal3 and Vhs3 are moonlighting proteins, acting both as inhibitors of the serine/threonine protein phosphatase Ppz1 and as subunits (together with Cab3) of the unique heterotrimeric phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme of Hemiascomycetous yeast. Both these roles are essential: PPCDC catalyses the third step of coenzyme A biosynthesis, while Ppz1 inhibition is required for regulation of monovalent cation homeostasis. However, the mechanisms by which these proteins’ disparate activities are regulated are not well understood. The PPCDC domains (PDs) of Hal3, Vhs3 and Cab3 constitute the minimum requirement for these proteins to show both PPCDC activity and, in the case of Hal3 and Vhs3, to bind to Ppz1. Using these PD proteins as a model system to study the possibility of dynamic interchange between these roles, we provide evidence that Hal3 binds Ppz1 as a monomer (1:1 stoichiometry), requiring it to deoligomerize from its usual homo- and heterotrimeric states (the latter having PPCDC activity). This de-oligomerization is made possible by structural features that set Hal3 apart from Vhs3, increasing its ability to undergo monomer exchange. These findings suggest that oligomer interchange may be a significant factor in the functional regulation of these proteins and their various unrelated (moonlighting) functions.
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    More than a vitamin : walks along an essential pathway
    (Stellenbosch : Stellenbosch University, 2014-03) Strauss, Erick
    Erick Strauss, born on 4 November 1975 and raised in Pretoria, attended the University of Pretoria from 1994 to 1997 where he obtained his BSc (majoring in chemistry and biochemistry) and BSc(Hons) (in chemistry) degrees, both cum laude. He subsequently moved to the USA in 1998 to pursue his graduate studies at Cornell University in Ithaca, NY, where he worked on the biosynthesis of coenzyme A with Prof Tadhg Begley. He obtained a PhD in Chemistry and Chemical Biology from Cornell in 2003. He returned to South Africa in the same year to accept an offer from Stellenbosch University to establish his own research group in the Department of Chemistry and Polymer Science. In 2008 he moved to the Department of Biochemistry (also at Stellenbosch University) as associate professor, and was promoted to full professor in 2013. Since the start of his independent career he has trained 11 MSc students (one as co-supervisor) and nine PhD students (one as co-promotor); he currently leads a group of four PhD students and four postdoctoral fellows. Erick is regarded as a leading authority on the biosynthesis and enzymology of the essential metabolic cofactor coenzyme A, as well as of the design, discovery and development of antimicrobial agents that target this pathway. His publications, which have attracted a total of more than 680 citations (h-index of 12), include articles in prestigious journals such as the Proceedings of the National Academy of the USA (PNAS), the Journal of the American Chemical Society (JACS) and two articles in Nature Chemical Biology. One of these is a commentary piece chosen as one of ten winning entries (one of only two from outside the United States) submitted by young scientists active in the field in which they expounded their vision of the future ‘Grand Challenges’ in the field of Chemical Biology. Erick currently holds a B3-rating from the NRF. Erick is a recipient of the DuPont Prize for Excellence in Teaching from Cornell University (1999); the Rector’s Award for Excellence in Teaching from Stellenbosch University (2007); the President’s Award from the South African National Research Foundation (2008); the Beckman-Coulter Silver Medal from the South African Society for Biochemistry and Molecular Biology (2010); and the Raikes Medal from the South African Chemical Institute (2013). In 2012 he was elected as a founding member of the South African Young Academy of Science. Since 2009 he is also husband to Suzanne and since 2012 father to Matteo – perhaps his biggest (and ongoing!) achievements to date.
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    Mutations at the hydrophobic core affect Hal3 trimer stability, reducing its Ppz1 inhibitory capacity but not its PPCDC moonlighting function
    (Nature Research, 2018-10-02) Santolaria, Carlos; Velazquez, Diego; Strauss, Erick; Arino, Joaquin
    S. cerevisiae Hal3 (ScHal3) is a moonlighting protein that, is in its monomeric state, regulates the Ser/Thr protein phosphatase Ppz1, but also joins ScCab3 (and in some instances the Hal3 paralog Vhs3) to form an unusual heterotrimeric phosphopantothenoylcysteine decarboxylase (PPCDC) enzyme. PPCDC is required for CoA biosynthesis and in most eukaryotes is a homotrimeric complex with three identical catalytic sites at the trimer interfaces. However, in S. cerevisiae the heterotrimeric arrangement results in a single functional catalytic center. Importantly, the specific structural determinants that direct Hal3’s oligomeric state and those required for Ppz1 inhibition remain largely unknown. We mutagenized residues in the predicted hydrophobic core of ScHal3 (L403–L405) and the plant Arabidopsis thaliana Hal3 (AtHal3, G115–L117) oligomers and characterized their properties as PPCDC components and, for ScHal3, also as Ppz1 inhibitor. We found that in AtHal3 these changes do not affect trimerization or PPCDC function. Similarly, mutation of ScHal3 L403 has no effect. In contrast, ScHal3 L405E fails to form homotrimers, but retains the capacity to bind Cab3—explaining its ability to rescue a hal3 vhs3 synthetically lethal mutation. Remarkably, the L405E mutation decreases Hal3’s ability to interact with and to inhibit Ppz1, confirming the importance of the oligomer/monomer equilibrium in Hal3’s Ppz1 regulating function.
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    Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues
    (Public Library of Science, 2018-04-03) Tjhin, Erick T.; Spry, Christina; Sewell, Alan L.; Hoegl, Annabelle; Barnard, Leanne; Sexton, Anna E.; Siddiqui, Ghizal; Howieson, Vanessa M.; Maier, Alexander G.; Creek, Darren J.; Strauss, Erick; Marquez, Rodolfo; Auclair, Karina; Saliba, Kevin J.; Phillips, Margaret A.
    The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ-15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA-utilising enzymes.
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    Pantothenamides are potent, on-target inhibitors of plasmodium falciparum growth when serum pantetheinase is inactivated
    (PLoS, 2013-02) Spry, Christina; Macuamule, Cristiano; Lin, Zhiyang; Virga, Kristopher G.; Lee, Richard E.; Strauss, Erick; Saliba, Kevin J.
    Growth of the virulent human malaria parasite Plasmodium falciparum is dependent on an extracellular supply of pantothenate (vitamin B5) and is susceptible to inhibition by pantothenate analogues that hinder pantothenate utilization. In this study, on the hunt for pantothenate analogues with increased potency relative to those reported previously, we screened a series of pantothenamides (amide analogues of pantothenate) against P. falciparum and show for the first time that analogues of this type possess antiplasmodial activity. Although the active pantothenamides in this series exhibit only modest potency under standard in vitro culture conditions, we show that the potency of pantothenamides is selectively enhanced when the parasite culture medium is pre-incubated at 37uC for a prolonged period. We present evidence that this finding is linked to the presence in Albumax II (a serum-substitute routinely used for in vitro cultivation of P. falciparum) of pantetheinase activity: the activity of an enzyme that hydrolyzes the pantothenate metabolite pantetheine, for which pantothenamides also serve as substrates. Pantetheinase activity, and thereby pantothenamide degradation, is reduced following incubation of Albumax II-containing culture medium for a prolonged period at 37uC, revealing the true, submicromolar potency of pantothenamides. Importantly we show that the potent antiplasmodial effect of pantothenamides is attenuated with pantothenate, consistent with the compounds inhibiting parasite proliferation specifically by inhibiting pantothenate and/or CoA utilization. Additionally, we show that the pantothenamides interact with P. falciparum pantothenate kinase, the first enzyme involved in converting pantothenate to coenzyme A. This is the first demonstration of on-target antiplasmodial pantothenate analogues with sub-micromolar potency, and highlights the potential of pantetheinase-resistant pantothenamides as antimalarial agents.
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    Vitamin in the crosshairs : targeting pantothenate and coenzyme a biosynthesis for new antituberculosis agents
    (Frontiers Media, 2020) Butman, Hailey S.; Kotze, Timothy J.; Dowd, Cynthia S.; Strauss, Erick
    ENGLISH ABSTRACT: Despite decades of dedicated research, there remains a dire need for new drugs against tuberculosis (TB). Current therapies are generations old and problematic. Resistance to these existing therapies results in an ever-increasing burden of patients with disease that is difficult or impossible to treat. Novel chemical entities with new mechanisms of action are therefore earnestly required. The biosynthesis of coenzyme A (CoA) has long been known to be essential in Mycobacterium tuberculosis (Mtb), the causative agent of TB. The pathway has been genetically validated by seminal studies in vitro and in vivo. In Mtb, the CoA biosynthetic pathway is comprised of nine enzymes: four to synthesize pantothenate (Pan) from L-aspartate and α-ketoisovalerate; five to synthesize CoA from Pan and pantetheine (PantSH). This review gathers literature reports on the structure/mechanism, inhibitors, and vulnerability of each enzyme in the CoA pathway. In addition to traditional inhibition of a single enzyme, the CoA pathway offers an antimetabolite strategy as a promising alternative. In this review, we provide our assessment of what appear to be the best targets, and, thus, which CoA pathway enzymes present the best opportunities for antitubercular drug discovery moving forward.