Structure-guided discovery of pharmacological chaperones targeting protein conformational and misfolding diseases

McCorvie, Thomas J.; Yue, Wyatt W.

doi:10.1016/b978-0-12-819132-3.00013-0

Cited by 4 publications

(4 citation statements)

References 138 publications

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“…The procedures to identify lead compounds as potential PCs can be widely classified in two groups: experimental and computational-structure guided screenings [ 103 , 104 , 105 , 106 ]. The possible route to finding PCs in galactosemia is illustrated in Figure 3 .…”

Section: Towards the Discovery Of Pharmacological Chaperones For Gmentioning

confidence: 99%

Galactosemia: Towards Pharmacological Chaperones

Banford

McCorvie

Pey

et al. 2021

JPM

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Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.

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Section: Towards the Discovery Of Pharmacological Chaperones For Gmentioning

confidence: 99%

Galactosemia: Towards Pharmacological Chaperones

Banford

McCorvie

Pey

et al. 2021

JPM

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“…10,11 Ligands of ALDH4A1 could potentially be used as pharmacological chaperones to stabilize the misfolded variants of ALDH4A1 produced in patients with hyperprolinemia II. 12,13 A recent study discovered that ALDH4A1 was significantly elevated in the plasma of atherosclerosis-prone Ldlr À / À mice as well as atherosclerotic tissue from humans, and the administration of an anti-ALDH4A1 antibody delayed atherosclerosis progression in Ldlr À / À mice. 14 These results suggest that anti-ALDH4A1 antibodies, and potentially ALDH4A1 inhibitors, may have therapeutic value in cardiovascular disease.…”

Section: Introductionmentioning

confidence: 99%

“…Inherited mutations in the ALDH4A1 gene cause hyperprolinemia II, a metabolic disorder that can result in neurological problems, including intellectual disability 10,11 . Ligands of ALDH4A1 could potentially be used as pharmacological chaperones to stabilize the misfolded variants of ALDH4A1 produced in patients with hyperprolinemia II 12,13 . A recent study discovered that ALDH4A1 was significantly elevated in the plasma of atherosclerosis‐prone Ldlr − / − mice as well as atherosclerotic tissue from humans, and the administration of an anti‐ALDH4A1 antibody delayed atherosclerosis progression in Ldlr − / − mice 14 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

et al. 2021

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Aldehyde dehydrogenase 4A1 (ALDH4A1) catalyzes the final steps of both proline and hydroxyproline catabolism. It is a dual substrate enzyme that catalyzes the NAD + -dependent oxidations of L-glutamate-γ-semialdehyde to L-glutamate (proline metabolism), and 4-hydroxy-L-glutamate-γ-semialdehyde to 4-erythro-hydroxy-L-glutamate (hydroxyproline metabolism). Here we investigated the inhibition of mouse ALDH4A1 by the six stereoisomers of proline and 4-hydroxyproline using steady-state kinetics and X-ray crystallography. Trans-4-hydroxy-L-proline is the strongest of the inhibitors studied, characterized by a competitive inhibition constant of 0.7 mM, followed by L-proline (1.9 mM). The other compounds are very weak inhibitors (approximately 10 mM or greater). Insight into the selectivity for L-stereoisomers was obtained by solving crystal structures of ALDH4A1 complexed with trans-4-hydroxy-L-proline and trans-4-hydroxy-D-proline. The structures suggest that the 10-fold greater preference for the L-stereoisomer is due to a serine residue that hydrogen bonds to the amine group of trans-4-hydroxy-L-proline. In contrast, the amine group of the D-stereoisomer lacks a direct interaction with the enzyme due to a different orientation of the pyrrolidine ring. These results suggest that hydroxyproline catabolism is subject to substrate inhibition by trans-4-hydroxy-L-proline, analogous to the known inhibition of proline catabolism by L-proline. Also, drugs targeting the first enzyme of hydroxyproline catabolism, by elevating the level of trans-4-hydroxy-L-proline, may inadvertently impair proline catabolism by the inhibition of ALDH4A1.

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“…Disease-associated variants can have altered protein flexibility, substrate/cofactor binding or their posttranslational modification pattern. [13] In MANSA, more than 130 pathogenic variants have been detected from which 54 are point mutations described to alter the normal intracellular processing and/or the 3D structure of the enzyme. [14] As an example, the frequent R750W mutation (in more than 20% of MANSA patients) prevents the correct folding of the enzyme, and mutations like D74E, H200L or H200N alter totally the coordination sphere of the metal ion at the active site.…”

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confidence: 99%

Digging out the molecular connections between the active site of human lysosomal alpha-mannosidase and its pathophysiology

Geronimo

Alonso-Gil

Žagrović

et al. 2022

Preprint

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Human lysosomal alpha-mannosidase (hLAMAN) is a paradigmatic example of how few missense mutations can critically affect normal catabolism in the lysosome and cause the severe condition named alpha-mannosidosis. Here we have made use of computational chemistry methods to unveil the molecular basis of 4 missense mutations in hLAMAN with pathological consequences. We have simulated for the first time the all-atom catalytic reaction mechanism of hLAMAN by means of quantum mechanics/molecular mechanics metadynamics. Second, we show how the catalytically inactive variant D74E presents a significant increase of the free energy barrier. Third, we have identified that the D159N and E402K mutations are connected with the active site movement. Finally, we show that mutation R229W does not alter the balance between the hydrophilic and hydrophobic solvent accessible surface area in the protein, but does affect the active site dynamics. Our findings open up new opportunities for treatment of mannosidosis.

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Structure-guided discovery of pharmacological chaperones targeting protein conformational and misfolding diseases

Cited by 4 publications

References 138 publications

Galactosemia: Towards Pharmacological Chaperones

Galactosemia: Towards Pharmacological Chaperones

Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

Digging out the molecular connections between the active site of human lysosomal alpha-mannosidase and its pathophysiology

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