Morpheeins – a new structural paradigm for allosteric regulation

Jaffe, Eileen K.

doi:10.1016/j.tibs.2005.07.003

Cited by 137 publications

(177 citation statements)

References 36 publications

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“…In plants, an allosteric magnesium ion favors octamer formation by binding at a subunit interface not present in the hexamer (2). The term "morpheeins" has been used to describe oligomers that can disassemble, change shape in the dissociated state, and reassemble to a structurally and functionally distinct oligomer (5). Fig.…”

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Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase

Jaffe

Shanmugam

Gardberg

et al. 2011

Journal of Biological Chemistry

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Porphobilinogen synthase (PBGS) is essential for heme biosynthesis, but the enzyme of the protozoan parasite Toxoplasma gondii (TgPBGS) differs from that of its human host in several important respects, including subcellular localization, metal ion dependence, and quaternary structural dynamics. We have solved the crystal structure of TgPBGS, which contains an octamer in the crystallographic asymmetric unit. Crystallized in the presence of substrate, each active site contains one molecule of the product porphobilinogen. Unlike prior structures containing a substrate-derived heterocycle directly bound to an active site zinc ion, the productbound TgPBGS active site contains neither zinc nor magnesium, placing in question the common notion that all PBGS enzymes require an active site metal ion. Unlike human PBGS, the TgPBGS octamer contains magnesium ions at the intersections between pro-octamer dimers, which are presumed to function in allosteric regulation. TgPBGS includes N-and C-terminal regions that differ considerably from previously solved crystal structures. In particular, the C-terminal extension found in all apicomplexan PBGS enzymes forms an intersubunit ␤-sheet, stabilizing a pro-octamer dimer and preventing formation of hexamers that can form in human PBGS. The TgPBGS structure suggests strategies for the development of parasite-selective PBGS inhibitors.The myriad forms of cyclic and linear tetrapyrroles, including heme, chlorophyll, siroheme, cobalamine (B 12 ), and the phycobilins, are essential for energy production/utilization in virtually all life forms. Tetrapyrrole biosynthesis pathways are complex and phylogenetically variable, suggesting the potential for species-selective control (1). The universal portion of this pathway consists of only three reactions, the first of which involves biosynthesis of the monopyrrole porphobilinogen from two molecules of 5-aminolevulinic acid (ALA) 3 (Fig. 1), catalyzed by porphobilinogen synthase (PBGS; EC 4.2.1.24; also known as 5-aminolevulinic acid dehydratase or ALAD). The photoreactive and toxic nature of tetrapyrrole biosynthesis intermediates mandates close regulation of this pathway, and various mechanisms are used for control. We recently have described an unusual mechanism of allosteric regulation involving transition between a high activity PBGS octamer and a low activity hexamer (2-4). In plants, an allosteric magnesium ion favors octamer formation by binding at a subunit interface not present in the hexamer (2). The term "morpheeins" has been used to describe oligomers that can disassemble, change shape in the dissociated state, and reassemble to a structurally and functionally distinct oligomer (5). Fig. 2 illustrates the quaternary structure dynamics of plant and mammalian PBGS, using the human structure by way of example. "Hugging" and "detached" dimers (pathway A) are observed as the asymmetric crystallographic units for wild type and mutant forms of human PBGS (PDB codes 1E51 and 1PV8, respectively (2, 6)). The structure of the physiologicall...

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Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase

Jaffe

Shanmugam

Gardberg

et al. 2011

Journal of Biological Chemistry

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“…Misregulation of the human PBGS quaternary structure equilibrium is associated with porphyric disease (8). Proteins exhibiting such alternative quaternary structure assemblies are called "morpheeins" (9).…”

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Plastid-associated Porphobilinogen Synthase from Toxoplasma gondii

Shanmugam

Ramirez

et al. 2010

Journal of Biological Chemistry

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Apicomplexan parasites (including Plasmodium spp. and Toxoplasma gondii) employ a four-carbon pathway for de novo heme biosynthesis, but this pathway is distinct from the animal/ fungal C4 pathway in that it is distributed between three compartments: the mitochondrion, cytosol, and apicoplast, a plastid acquired by secondary endosymbiosis of an alga. Parasite porphobilinogen synthase (PBGS) resides within the apicoplast, and phylogenetic analysis indicates a plant origin. The PBGS family exhibits a complex use of metal ions (Zn 2؉ and Mg 2؉ ) and oligomeric states (dimers, hexamers, and octamers). Recombinant T. gondii PBGS (TgPBGS) was purified as a stable ϳ320-kDa octamer, and low levels of dimers but no hexamers were also observed. The enzyme displays a broad activity peak (pH 7-8.5), with a K m for aminolevulinic acid of ϳ150 M and specific activity of ϳ24 mol of porphobilinogen/mg of protein/h. Like the plant enzyme, TgPBGS responds to Mg 2؉ but not Zn 2؉ and shows two Mg 2؉ affinities, interpreted as tight binding at both the active and allosteric sites. Unlike other Mg 2؉ -binding PBGS, however, metal ions are not required for TgPBGS octamer stability. A mutant enzyme lacking the C-terminal 13 amino acids distinguishing parasite PBGS from plant and animal enzymes purified as a dimer, suggesting that the C terminus is required for octamer stability. Parasite heme biosynthesis is inhibited (and parasites are killed) by succinylacetone, an active site-directed suicide substrate. The distinct phylogenetic, enzymatic, and structural features of apicomplexan PBGS offer scope for developing selective inhibitors of the parasite enzyme based on its quaternary structure characteristics.

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“…We predict that regulation of enzyme function by control of non-additive assembly states in vivo may be common throughout nature and protein class, termed the morpheein model of allostery. 6 We also consider the fact that it may be possible to inhibit the function of an essential protein or enzyme in a pathogen without interfering with the corresponding target in the host, providing a new means for allosteric anti-infective drug action. Therefore, application of the morpheein model of allostery to drug discovery may provide novel anti-infective therapy on a case-by-case basis depending on the differential regulation of protein assembly state in the pathogen vs. the host.…”

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Pseudomonas aeruginosa porphobilinogen synthase assembly state regulators: hit discovery and initial SAR studies

Reitz

Ramirez²,

Stith³

et al. 2010

Arkivoc

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Porphobilinogen synthase (PBGS) catalyzes the first common step in the biosynthesis of the essential heme, chlorophyll and vitamin B 12 heme pigments. PBGS activity is regulated by assembly state, with certain oligomers exhibiting biological activity and others either partially or completely inactive, affording an innovative means of allosteric drug action. Pseudomonas aeruginosa PBGS is functionally active as an octamer, and inactive as a dimer. We have identified a series of compounds that stabilize the inactive P. aeruginosa dimer by a computational prescreen followed by native PAGE gel mobility shift analysis. From those results, we have prepared related thiadiazoles and evaluated their ability to regulate P. aeruginosa PBGS assembly state.

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Morpheeins – a new structural paradigm for allosteric regulation

Cited by 137 publications

References 36 publications

Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase

Crystal Structure of Toxoplasma gondii Porphobilinogen Synthase

Plastid-associated Porphobilinogen Synthase from Toxoplasma gondii

Pseudomonas aeruginosa porphobilinogen synthase assembly state regulators: hit discovery and initial SAR studies

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