Inter-domain Communication of Human Cystathionine β-Synthase

McCorvie, Thomas J.; Kopec, J.; Hyung, Suk Joon; Fitzpatrick, Fiona; Feng, Xidong; Termine, Daniel J.; Strain-Damerell, Claire; Vollmar, M.; Fleming, James; Janz, Jay M.; Bulawa, Christine E.; Yue, Wyatt W.

doi:10.1074/jbc.m114.610782

Cited by 52 publications

(59 citation statements)

References 36 publications

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“…A similar phenomenon of domain organization is found in several eukaryotic enzymes, for example those involved in amino acid metabolism (e.g. cystathionine β-synthase, CBS 36 ; phenylalanine hydroxylase, PAH 37 ), whereby the additional metabolite-binding modules, not found in their bacterial counterparts, serve to fine-tune catalysis in response to the more intricate higher eukaryotic metabolic and signalling cues. We propose that MTHFR belongs to this class of allosteric enzymes that share a common mechanism—to regulate catalysis through steric sequestration of the catalytic site, in a ligand-dependent manner (SAM for MTHFR and CBS; phenylalanine for PAH).…”

Section: Discussionmentioning

confidence: 59%

Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition

et al. 2018

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The folate and methionine cycles are crucial for biosynthesis of lipids, nucleotides and proteins, and production of the methyl donor S-adenosylmethionine (SAM). 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a key regulatory connection between these cycles, generating 5-methyltetrahydrofolate for initiation of the methionine cycle, and undergoing allosteric inhibition by its end product SAM. Our 2.5 Å resolution crystal structure of human MTHFR reveals a unique architecture, appending the well-conserved catalytic TIM-barrel to a eukaryote-only SAM-binding domain. The latter domain of novel fold provides the predominant interface for MTHFR homo-dimerization, positioning the N-terminal serine-rich phosphorylation region near the C-terminal SAM-binding domain. This explains how MTHFR phosphorylation, identified on 11 N-terminal residues (16 in total), increases sensitivity to SAM binding and inhibition. Finally, we demonstrate that the 25-amino-acid inter-domain linker enables conformational plasticity and propose it to be a key mediator of SAM regulation. Together, these results provide insight into the molecular regulation of MTHFR.

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Section: Discussionmentioning

confidence: 59%

Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition

et al. 2018

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“…Lessons could therefore be learnt from this and other examples of metabolic enzymes (e.g. cystathionine β-synthase, the cause of homocystinuria 42 ; porphobilinogen synthase, the cause of ALAD porphyria 43 ), for the design of novel PC molecules that target the allosteric domains as a stabilization strategy.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain

Patel

Kopec

Fitzpatrick

et al. 2016

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The multi-domain enzyme phenylalanine hydroxylase (PAH) catalyzes the hydroxylation of dietary I-phenylalanine (Phe) to I-tyrosine. Inherited mutations that result in PAH enzyme deficiency are the genetic cause of the autosomal recessive disorder phenylketonuria. Phe is the substrate for the PAH active site, but also an allosteric ligand that increases enzyme activity. Phe has been proposed to bind, in addition to the catalytic domain, a site at the PAH N-terminal regulatory domain (PAH-RD), to activate the enzyme via an unclear mechanism. Here we report the crystal structure of human PAH-RD bound with Phe at 1.8 Å resolution, revealing a homodimer of ACT folds with Phe bound at the dimer interface. This work delivers the structural evidence to support previous solution studies that a binding site exists in the RD for Phe, and that Phe binding results in dimerization of PAH-RD. Consistent with our structural observation, a disease-associated PAH mutant impaired in Phe binding disrupts the monomer:dimer equilibrium of PAH-RD. Our data therefore support an emerging model of PAH allosteric regulation, whereby Phe binds to PAH-RD and mediates the dimerization of regulatory modules that would bring about conformational changes to activate the enzyme.

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“…Indeed, the interaction between the core and regulatory domains has been shown to involve (i) hydrophobic interactions with residues from the C-terminal domain CBS2 motif and (ii) H-bonds with residues from the C-terminal domain CBS1 motif [ 44 , 46 ]. Notably, in the presence of AdoMet, the two C-terminal domains assemble together in a “disc”-like form, similarly to the constitutively activated Drosophila melanogaster AdoMet-free CBS [ 47 ], the substrate entrance opens, and access to the active site is enhanced ( Figure 4(c) ), thus increasing enzymatic activity [ 44 , 46 , 48 ]. Each Bateman module contains two putative AdoMet-binding cavities (S1 and S2) with different binding affinities [ 49 ].…”

Section: Hydrogen Sulfide Metabolism In Human Physiologymentioning

confidence: 99%

Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology

Giuffrè

Vicente

2018

Oxidative Medicine and Cellular Longevity

125

104

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Hydrogen sulfide (H2S) has emerged as a relevant signaling molecule in physiology, taking its seat as a bona fide gasotransmitter akin to nitric oxide (NO) and carbon monoxide (CO). After being merely regarded as a toxic poisonous molecule, it is now recognized that mammalian cells are equipped with sophisticated enzymatic systems for H2S production and breakdown. The signaling role of H2S is mainly related to its ability to modify different protein targets, particularly by promoting persulfidation of protein cysteine residues and by interacting with metal centers, mostly hemes. H2S has been shown to regulate a myriad of cellular processes with multiple physiological consequences. As such, dysfunctional H2S metabolism is increasingly implicated in different pathologies, from cardiovascular and neurodegenerative diseases to cancer. As a highly diffusible reactive species, the intra- and extracellular levels of H2S have to be kept under tight control and, accordingly, regulation of H2S metabolism occurs at different levels. Interestingly, even though H2S, NO, and CO have similar modes of action and parallel regulatory targets or precisely because of that, there is increasing evidence of a crosstalk between the three gasotransmitters. Herein are reviewed the biochemistry, metabolism, and signaling function of hydrogen sulfide, as well as its interplay with the other gasotransmitters, NO and CO.

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Inter-domain Communication of Human Cystathionine β-Synthase

Cited by 52 publications

References 36 publications

Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition

Structural basis for the regulation of human 5,10-methylenetetrahydrofolate reductase by phosphorylation and S-adenosylmethionine inhibition

Structural basis for ligand-dependent dimerization of phenylalanine hydroxylase regulatory domain

Hydrogen Sulfide Biochemistry and Interplay with Other Gaseous Mediators in Mammalian Physiology

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