Controlling the delicate balance of tetrapyrrole biosynthesis

Yin, Liang; Bauer, Carl E.

doi:10.1098/rstb.2012.0262

Cited by 38 publications

(43 citation statements)

References 79 publications

(133 reference statements)

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“…Thus, photohydrolysis of the upper 5′-deoxyadenosyl Co ligand, followed by formation of a stable His adduct, may be a common mechanism of this class of B 12 -dependent photoreceptors. In the case of AerR, subsequent regulation of gene expression occurs through the formation of a stable interaction between B 12 -bound AerR and a well-characterized repressor of photosystem gene expression termed CrtJ [7, 8]. This interaction affects the oligomerization state of CrtJ to alter its DNA binding affinity (Fig.…”

Section: B12 Has a Newly Defined Role Of Controlling Of Gene Expressimentioning

confidence: 99%

Cobalamin's (Vitamin B12) Surprising Function as a Photoreceptor

Cheng

Yamamoto

Bauer

2016

Trends in Biochemical Sciences

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Summary Cobalamin (Vitamin B12) is an adenosyl-or methyl-donating cofactor for many enzymes, yet many proteins with unknown or non-enzymatic function also contain B12 binding domains. Recent studies show that light excitation energy can promote covalent linkage of B12 to transcription factors with this linkage affecting gene expression. Thus B12 now has a newly described regulatory function. Here, our bioinformatics analysis reveals other transcription factors, photoreceptors, kinases and oxygen sensors that harbor a B12-binding domain that could potentially also regulate activity in response to light absorption.

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Section: B12 Has a Newly Defined Role Of Controlling Of Gene Expressimentioning

confidence: 99%

Cobalamin's (Vitamin B12) Surprising Function as a Photoreceptor

Cheng

Yamamoto

Bauer

2016

Trends in Biochemical Sciences

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“…PBGS catalyzes the first of three common steps in tetrapyrrole biosynthesis, after which there is extensive pathway diversity. 3 The enzyme catalyzed reaction is an asymmetric condensation of two molecules of 5-aminolevulinic acid (ALA) 4 , which is biosynthesized either from succinyl-CoA and glycine or from glutamic acid. 5 The PBGS substrates are identified as P-side ALA and A-side ALA to indicate their fate in the product (described in Fig.…”

Section: Introductionmentioning

confidence: 99%

The Remarkable Character of Porphobilinogen Synthase

Jaffe

2016

Acc. Chem. Res.

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Conspectus Porphobilinogen synthase (PBGS), also known as 5-aminolevulinate dehydratase, is an essential enzyme in the biosynthesis of all tetrapyrroles, which function in respiration, photosynthesis, and methanogenesis. Throughout evolution, PBGS adapted to a diversity of cellular niches and evolved to use an unusual variety of metal ions both for catalytic function and to control protein multimerization. With regard to the active site, some PBGS require Zn2+; a subset of those, including human PBGS, contain a constellation of cysteine residues that acts as a sink for the environmental toxin Pb2+. PBGS that do not require the soft metal ion Zn2+ at the active site, instead are suspected of using the hard metal, Mg2+. The most unexpected property of the PBGS family of enzymes is a dissociative allosteric mechanism that utilizes an equilibrium of architecturally and functionally distinct protein assemblies. The high-activity assembly is an octamer in which inter-subunit interactions modulate active-site lid motion. This octamer can dissociate to dimer, the dimer can undergo a hinge twist, and the twisted dimer can assemble to a low-activity hexamer. The hexamer does not have the intersubunit interactions required to stabilize a closed conformation of the active site lid. PBGS active site chemistry benefits from a closed lid because porphobilinogen biosynthesis includes Schiff base formation, which requires deprotonated lysine amino groups. N-terminal and C-terminal sequence extensions dictate whether or not a specific species of PBGS can sample the hexameric assembly. The bulk of species (nearly all except animals and yeasts) use Mg2+ as an allosteric activator. Mg2+ functions allosterically by binding to an intersubunit interface that is present in the octamer but absent in the hexamer. This conformational selection allosteric mechanism is purported to be essential to avoid the untimely accumulation of phototoxic chlorophyll precursors in plants. For those PBGS that do not use the allosteric Mg2+, there is a spatially equivalent arginine derived guanidium group. Deprotonation of this residue promotes formation of the hexamer and accounts for the basic arm of the bell-shaped pH vs. activity profile of human PBGS. A human inborn error of metabolism, known as ALAD porphyria, is attributed to PBGS variants that favor the hexameric assembly. The existence of one such variant, F12L, which dramatically stabilizes the human PBGS hexamer, allowed crystal structure determination for the hexamer. Without this crystal structure, and octameric PBGS structures containing the allosteric Mg2+, it would have been difficult to decipher the structural basis for PBGS allostery. The requirement for multimer dissociation as an intermediate step in PBGS allostery was established by monitoring subunit disproportionation during the turnover-dependent transition of heteromeric PBGS (comprised of human wild type and F12L) from hexamer to octamer. One outcome of these studies was the definition of the dissociative morpheein model of protei...

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“…One well-studied redox-and lightregulated transcription factor that controls this process is PpsR (also called CrtJ in some species) (5)(6)(7)(8)(9). PpsR/CrtJ homologs are linked to a cluster of genes coding for enzymes involved in bacteriochlorophyll and carotenoid biosynthesis in almost all purple phototrophic bacteria.…”

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Members of the PpaA/AerR Antirepressor Family Bind Cobalamin

Vermeulen

Bauer

2015

J Bacteriol

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PpaA from Rhodobacter sphaeroides is a member of a family of proteins that are thought to function as antirepressors of PpsR, a widely disseminated repressor of photosystem genes in purple photosynthetic bacteria. PpaA family members exhibit sequence similarity to a previously defined SCHIC (sensor containing heme instead of cobalamin) domain; however, the tetrapyrrolebinding specificity of PpaA family members has been unclear, as R. sphaeroides PpaA has been reported to bind heme while the Rhodobacter capsulatus homolog has been reported to bind cobalamin. In this study, we reinvestigated tetrapyrrole binding of PpaA from R. sphaeroides and show that it is not a heme-binding protein but is instead a cobalamin-binding protein. We also use bacterial two-hybrid analysis to show that PpaA is able to interact with PpsR and activate the expression of photosynthesis genes in vivo. Mutations in PpaA that cause loss of cobalamin binding also disrupt PpaA antirepressor activity in vivo. We also tested a number of PpaA homologs from other purple bacterial species and found that cobalamin binding is a conserved feature among members of this family of proteins. IMPORTANCECobalamin (vitamin B 12 ) has only recently been recognized as a cofactor that affects gene expression by interacting in a lightdependent manner with transcription factors. A group of related antirepressors known as the AppA/PpaA/AerR family are known to control the expression of photosynthesis genes in part by interacting with either heme or cobalamin. The specificity of which tetrapyrroles that members of this family interact with has, however, remained cloudy. In this study, we address the tetrapyrrole-binding specificity of the PpaA/AerR subgroup and establish that it preferentially binds cobalamin over heme.

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Controlling the delicate balance of tetrapyrrole biosynthesis

Cited by 38 publications

References 79 publications

Cobalamin's (Vitamin B12) Surprising Function as a Photoreceptor

Cobalamin's (Vitamin B12) Surprising Function as a Photoreceptor

The Remarkable Character of Porphobilinogen Synthase

Members of the PpaA/AerR Antirepressor Family Bind Cobalamin

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