Effect of the Disease-Causing R266K Mutation on the Heme and PLP Environments of Human Cystathionine β‑Synthase

Cystathionine β-synthase (CBS) is an essential pyridoxal 5′-phosphate (PLP)-dependent enzyme of the transsulfuration pathway that condenses serine with homocysteine to form cystathionine; intriguingly, human CBS also contains a heme <i>b</i> cofactor of unknown function. Herein we describe the enzymatic and spectroscopic properties of a disease-associated R266K hCBS variant, which has an altered hydrogen-bonding environment. The R266K hCBS contains a low-spin, six-coordinate Fe­(III) heme bearing a His/Cys ligation motif, like that of WT hCBS; however, there is a geometric distortion that exists at the R266K heme. Using rR spectroscopy, we show that the Fe­(III)-Cys­(thiolate) bond is longer and weaker in R266K, as evidenced by an 8 cm^–1 downshift in the ν­(Fe–S) resonance. Presence of this longer and weaker Fe­(III)–Cys­(thiolate) bond is correlated with alteration of the fluorescence spectrum of the active PLP ketoenamine tautomer. Activity data demonstrate that, relative to WT, the R266K variant is more impaired in the alternative cysteine-synthesis reaction than in the canonical cystathionine-synthesis reaction. This diminished cysteine synthesis activity and a greater sensitivity to exogenous PLP correlate with the change in PLP environment. Fe–S­(Cys) bond weakening causes a nearly 300-fold increase in the rate of ligand switching upon reduction of the R266K heme. Combined, these data demonstrate cross talk between the heme and PLP active sites, consistent with previous proposals, revealing that alteration of the Arg²⁶⁶–Cys⁵² interaction affects PLP-dependent activity and dramatically destabilizes the ferrous thiolate-ligated heme complex, underscoring the importance of this hydrogen-bonding residue pair

TOI-2076 and TOI-1807: Two young, comoving planetary systems within 50 pc identified by TESS that are ideal candidates for further follow up

We report the discovery of two planetary systems around comoving stars: TOI-2076 (TIC 27491137) and TOI-1807 (TIC 180695581). TOI-2076 is a nearby (41.9 pc) multiplanetary system orbiting a young (204 ± 50 Myr), bright (K = 7.115 in TIC v8.1) start. TOI-1807 hosts a single transiting planet and is similarly nearby (42.58 pc), similarly young (180 ± 40 Myr ), and bright. Both targets exhibit significant, periodic variability due to starspots, characteristic of their young ages. Using photometric data collected by TESS we identify three transiting planets around TOI-2076 with radii of R b = 3.3 ± 0.04 R ⊕, R c = 4.4 ± 0.05 R ⊕, and R d = 4.1 ± 0.07 R ⊕. Planet TOI-2076b has a period of P b = 10.356 days. For both TOI-2076c and d, TESS observed only two transits, separated by a 2 yr interval in which no data were collected, preventing a unique period determination. A range of long periods (<17 days) are consistent with the data. We identify a short-period planet around TOI-1807 with a radius of R b = 1.8 ± 0.04 R ⊕ and a period of P b = 0.549 days. Their close proximity, and bright, cool host stars, and young ages make these planets excellent candidates for follow up. TOI-1807b is one of the best-known small (R < 2 R⊕) planets for characterization via eclipse spectroscopy and phase curves with JWST. TOI-1807b is the youngest ultra-short-period planet discovered to date, providing valuable constraints on formation timescales of short-period planets. Given the rarity of young planets, particularly in multiple-planet systems, these planets present an unprecedented opportunity to study and compare exoplanet formation, and young planet atmospheres, at a crucial transition age for formation theory