Allosteric inhibitors of HMG-CoA reductase, the key enzyme involved in cholesterol biosynthesis

Abstract

The corrole-based catalytic antioxidant reduced the cholesterol biosynthesis ability of macrophages, harvested from mice treated with it. and a non-redox active analogue of it affect the committed step of the biosynthetic pathway--the HMG-CoA reductase catalysed reaction--by acting as allosteric inhibitors of this key enzyme.

Energy-Related Small Molecule Activation Reactions: Oxygen Reduction and Hydrogen and Oxygen Evolution Reactions Catalyzed by Porphyrin- and Corrole-Based Systems

“…Corroles have been shown to be versatile trianionic ligands for the coordination of a number of transition metals and main group elements. − In these complexes, the central metals are usually in high-valent states, although the macrocycles are also noninnocent with significant radical character in many cases. Therefore, the special ability of corroles to stabilize high-valent transition metal ions forms a basis for better understanding corrole chemistry.…”

Tuned Amperometric Detection of Reduced β-Nicotinamide Adenine Dinucleotide by Allosteric Modulation of the Reductase Component of the p-Hydroxyphenylacetate Hydroxylase Immobilized within a Redox Polymer

“…In the case of biosensors employing allosteric redox enzymes, direct electrical connection of the protein to the signal-generating transducer interface is preferable to cascade detection schemes with multiple enzymes. Activatory and inhibitory allosteric modulation of redox enzymes have been reported for a number of systems, for example brain cytochrome P450 46A1 activation by neuroactive compounds, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by corrole, a natural tetrapyrolle-based antioxidant, and control of Cu-containing bacterial nitrate reductase by exogenous organochemical ligands . However, utilization of the allosteric behavior of redox enzymes for quantitative amperometric or voltammetric electroanalysis is, to the best of our knowledge, limited to one proof-of-principle study that used sophisticated protein engineering to convert a PQQ-glucose dehydrogenase into an allosteric electrochemical Ca 2+ sensor with a simple amperometric glucometer readout .…”

A cytotoxic and cytostatic gold(iii) corrole

“…Two methods for the preparation of gold(III) corroles have been reported: [ClAu(tht)] (tht = tetrahydrothiophene) was used for insertion into a b-brominated corrole in 85% yield, 16 whereas Au(OAc) 3 was utilized for the synthesis of several b-unsubstituted gold(III) triarylcorroles in 25-35% yield. 17 The above reagents, as well as chloroauric acid and its salts were tested in an attempted synthesis of 1-Au, but only gold(III) acetate led to the desired complex.…”

“…17 The above reagents, as well as chloroauric acid and its salts were tested in an attempted synthesis of 1-Au, but only gold(III) acetate led to the desired complex. The treatment of 2,17-bis-sulfonato-5,10,15-trispentafluorophenylcorrole (1-H 3 ) with excess of Au(OAc) 3 in pyridine at room temperature allowed the isolation of 1-Au in 25% yield (Scheme 1). 21 The electronic spectrum of 1-Au is similar to those of other metal complexes of the same corrole (Fig.…”

“…2 More recent health-related research has focused on the iron(III), manganese(III), aluminium(III), and gallium(III) complexes of 2,17-bis-sulfonato-5,10,15-trispentafluorophenylcorrole (Scheme 1: 1-Fe, 1-Mn, 1-Al, and 1-Ga). [3][4][5] These well characterized amphipolar complexes form tight conjugates with a variety of proteins that have been used as trafficking and cell penetrating vehicles in physiologically relevant media. 6 Closed-shell metallocorroles have been employed for optical imaging, whereas certain others exhibit pro-oxidant, anti-oxidant, and cell-killing properties, as follows: 1-Mn catalyzes the peroxidase-like enantioselective oxidation of sulfides by hydrogen peroxide, 7 1-Fe is the best synthetic catalyst reported to date for the catalase-like decomposition of hydrogen peroxide to water and molecular oxygen, 8 1-Al is a versatile optical imaging agent, 9 and 1-Ga is cytotoxic to breast cancer cells.…”