Diverse Clinical Compounds Alter the Quaternary Structure and Inhibit the Activity of an Essential Enzyme

Lawrence, Sarah H.; Selwood, Trevor; Jaffe, Eileen K.

doi:10.1002/cmdc.201100009

Cited by 17 publications

(34 citation statements)

References 37 publications

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“…8 Oligomer-stabilizing speciesselective PBGS inhibition has been documented. [14][15][16] This allosteric mechanism makes PBGS the prototype morpheein. 9,17 In humans, the equilibrium is correlated with the inborn error of metabolism known as ALAD porphyria and with toxic side effects of some drugs.…”

Section: Summary and Future Directionsmentioning

confidence: 98%

“…Hexamer-stabilizing inhibitors of human PBGS have been revealed through an in vitro native PAGE mobility shift screen of the Johns Hopkins Clinical Compound library of drugs in clinical use. 15 This screen revealed 12 drugs that stabilize the human PBGS hexamer and inhibit activity in vitro. 15 These drugs are nitrofurazone, tolfenamic acid, copper sulfate, flufenamic acid, rose Bengal, meclofenamic acid, 2,4-dinitroanisole, diclofenac, 3,5-dibromosalicylaldehyde, niflumic acid, bendroflumethiazide, and oxantel.…”

Section: Allosteric Inhibitionmentioning

confidence: 99%

“…15 This screen revealed 12 drugs that stabilize the human PBGS hexamer and inhibit activity in vitro. 15 These drugs are nitrofurazone, tolfenamic acid, copper sulfate, flufenamic acid, rose Bengal, meclofenamic acid, 2,4-dinitroanisole, diclofenac, 3,5-dibromosalicylaldehyde, niflumic acid, bendroflumethiazide, and oxantel. A related study revealed that the drugs clioquinol and iodoquinol also act to inhibit human PBGS through a mechanism that stabilizes the hexamer.…”

Section: Allosteric Inhibitionmentioning

confidence: 99%

“…7,8,11,15,16,[19][20][21]80 The "*" represents a change in the orientation of the N-terminal arm domain relative to the αβ-barrel domain. Human PBGS does not contain the C-terminal tail.…”

Section: B Pbgs Quaternary Structure Dynamicsmentioning

confidence: 99%

“…In PBGS from some species, structural components prevent the 2mer 2mer* transition. 10 The PBGS quaternary structure equilibrium has: (1) been correlated with a human inborn error of metabolism, 11 (2) been targeted for antimicrobial drug discovery, [12][13][14] (3) been correlated with drug side effects, 15,16 and (4) served as a prototype for the characterization of the unexpected quaternary structure dynamic characteristic of morpheeins. [17][18][19][20][21] This chapter provides an overview of the PBGS-catalyzed reaction, the myriad metals of PBGS, the structure of PBGS, the PBGS quaternary structure equilibrium, and how PBGS serves as a prototype for drug discovery efforts that target alternate quaternary structure assemblies.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The Dance of Porphobilinogen Synthase in the Control of Tetrapyrrole Biosynthesis

Jaffe¹,

Lawrence²

2013

Handbook of Porphyrin Science

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Section: Summary and Future Directionsmentioning

confidence: 98%

Section: Allosteric Inhibitionmentioning

confidence: 99%

Section: Allosteric Inhibitionmentioning

confidence: 99%

Section: B Pbgs Quaternary Structure Dynamicsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Dance of Porphobilinogen Synthase in the Control of Tetrapyrrole Biosynthesis

Jaffe¹,

Lawrence²

2013

Handbook of Porphyrin Science

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Porphobilinogen synthase: An equilibrium of different assemblies in human health

Jaffe

2020

Progress in Molecular Biology and Translational Science

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Porphobilinogen synthase (PBGS) is an essential enzyme that catalyzes an early step in heme biosynthesis. An unexpected human PBGS quaternary structure dynamic drove the definition of morpheeins, which are protein multimers that dissociate, change shape, and re-assemble differently with functional consequences. Each PBGS monomer has two domains that can reposition through a hinge motion. Human PBGS exists in an equilibrium among high activity octamer, low activity hexamer, and low mole-fraction dimer in which the hinge motion occurs. The dimer conformation dictates the multimer architecture. An octamer-specific inter-subunit interaction responds to pH, resulting in a pH-dependence to the octamer-hexamer equilibrium. An inborn error of metabolism, ALAD porphyria, is caused by single amino acid substitutions that stabilize the hexamer relative to octamer. Drugs that stabilize the PBGS hexamer result in a drug side effect that can exacerbate porphyria. PBGS is essential for all organisms that require respiration, photosynthesis, or methanogenesis. Consequently, phylogenetic variation in PBGS multimerization equilibria provides insight into how Nature has harnessed oligomeric variation in the control of protein function. The dynamic multimerization of PBGS revealed the morpheein mechanism for allostery, a structural basis for inborn errors of metabolism, a quaternary structure focus for drug discovery and/or drug side effects, and a pathway toward new antibiotics or herbicides. The fortuitous discovery of PBGS quaternary structure dynamics arose from characterization of a low-activity single amino acid variant that dramatically stabilized the hexamer, whose existence had previously gone unnoticed.

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Allostery and the dynamic oligomerization of porphobilinogen synthase

Jaffe

Lawrence

2012

Archives of Biochemistry and Biophysics

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The structural basis for allosteric regulation of porphobilinogen synthase (PBGS) is modulation of a quaternary structure equilibrium between octamer and hexamer (via dimers), which is represented schematically as 8mer ⇔ 2mer ⇔ 2mer* ⇔ 6mer*. The “*” represents a reorientation between two domains of each subunit that occurs in the dissociated state because it is sterically forbidden in the larger multimers. Allosteric effectors of PBGS are both intrinsic and extrinsic and are phylogenetically variable. In some species this equilibrium is modulated intrinsically by magnesium which binds at a site specific to the 8mer. In other species this equilibrium is modulated intrinsically by pH; the guanidinium group of an arginine being spatially equivalent to the allosteric magnesium ion. In humans, disease associated variants all shift the equilibrium toward the 6mer* relative to wild type. The 6mer* has a surface cavity that is not present in the 8mer and is proposed as a small molecule allosteric binding site. In silico and in vitro approaches have revealed species-specific allosteric PBGS inhibitors that stabilize the 6mer*. Some of these inhibitors are drugs in clinical use leading to the hypothesis that extrinsic allosteric inhibition of human PBGS could be a mechanism for drug side effects.

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Diverse Clinical Compounds Alter the Quaternary Structure and Inhibit the Activity of an Essential Enzyme

Cited by 17 publications

References 37 publications

The Dance of Porphobilinogen Synthase in the Control of Tetrapyrrole Biosynthesis

The Dance of Porphobilinogen Synthase in the Control of Tetrapyrrole Biosynthesis

Porphobilinogen synthase: An equilibrium of different assemblies in human health

Allostery and the dynamic oligomerization of porphobilinogen synthase

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