The active sites of metalloenzymes that catalyze O
2
-dependent reactions generally contain iron or copper ions. However, several enzymes are capable of activating O
2
at manganese or nickel centers ...instead, and a handful of dioxygenases exhibit activity when substituted with cobalt. This minireview summarizes the catalytic properties of oxygenases and oxidases with mononuclear Mn, Co, or Ni active sites, including oxalate-degrading oxidases, catechol dioxygenases, and quercetin dioxygenase. In addition, recent developments in the O
2
reactivity of synthetic Mn, Co, or Ni complexes are described, with an emphasis on the nature of reactive intermediates featuring superoxo-, peroxo-, or oxo-ligands. Collectively, the biochemical and synthetic studies discussed herein reveal the possibilities and limitations of O
2
activation at these three “overlooked” metals.
In spite of efforts to increase gender diversity across many science fields, women continue to encounter beliefs that they lack ability and talent. Undergraduate education is a critical time when ...peer influence may alter choice of majors and careers for women interested in science. Even in life science courses, in which women outnumber men, gender biases that emerge in peer-to-peer interactions during coursework may detract from women's interest and progress. This is the first study of which we are aware to document that women are outperforming men in both physical and life science undergraduate courses at the same institution, while simultaneously continuing to be perceived as less-able students. This is problematic because undergraduate women may not be able to escape gender-ability stereotypes even when they are outperforming men, which has important implications for 1) the recognition of women's achievements among their peers in undergraduate education and 2) retention of women in STEM disciplines and careers.
A nonheme Fe(ii) complex (1) that models substrate-bound cysteine dioxygenase (CDO) reacts with O
at -80 °C to yield a purple intermediate (2). Analysis with spectroscopic and computational methods ...determined that 2 features a thiolate-ligated Fe(iii) center bound to a superoxide radical, mimicking the putative structure of a key CDO intermediate.
There is well-established evidence that Mental Health First Aid (MHFA) training improves knowledge about how to support someone developing a mental health problem, but less evidence that this support ...improves the mental health of the recipient of aid. This randomised controlled trial aimed to assess the long-term effects of MHFA training of parents on the mental health of their adolescent children.
384 Australian parents of an adolescent aged 12-15 were randomised to receive either the 14-h Youth MHFA course or the 15-h Australian Red Cross Provide First Aid course. Outcomes were assessed at baseline, 1-year, and 2-year follow-up in both parents and adolescents. Primary outcomes were cases of adolescent mental health problems, and parental support towards their adolescent if they developed a mental health problem, rated by the parent and adolescent. Secondary outcomes included parent knowledge about mental health problems, intentions and confidence in supporting a young person, stigmatizing attitudes, and help-seeking for mental health problems.
Parent and adolescent reports showed no significant difference between training groups in the proportion of cases of adolescents with a mental health problem over time (ps > .05). There was also no significant difference between training groups in the quality of parental support provided to their adolescent at 1- or 2-year follow-up (ps > .05). In contrast, some secondary outcomes showed benefits from the Youth MHFA training relative to the control, with increased parental knowledge about mental health problems at 1-year (d = 0.43) and 2-year follow-up (d = 0.26), and increased confidence to help a young person (d = 0.26) and intentions to provide effective support (d = 0.22) at 1-year follow-up.
The study showed some improvements in mental health literacy in training recipients, but could not detect changes in the mental health of adolescents and the support provided to them by their parents if they had a mental health problem. However, there was a lack of power to detect primary outcome effects and therefore the question of whether MHFA training leads to better outcomes in the recipients of aid remains to be further explored.
ACTRN12612000390886 , registered retrospectively 5/4/2012.
Mental Health First Aid (MHFA) training teaches community members how to provide initial support to someone with a mental health problem. Key gaps in the evidence base supporting the training are the ...longevity of effects beyond 6 months, effects on mental health first aid behavior, and the impact of support on the recipient of aid. This study aimed to evaluate the effect of the Youth MHFA course 3 years after training.
384 Australian parents of an adolescent aged 12-15 were randomized to receive either the 14-h Youth MHFA course or the 15-h Australian Red Cross Provide First Aid course. This paper reports outcomes at baseline and 3 years later. Primary outcomes were cases of adolescent mental health problems, and parental support towards their adolescent if they developed a mental health problem, rated by the parent and adolescent. Secondary outcomes included parent knowledge about youth mental health problems, intentions and confidence in supporting a young person, stigmatizing attitudes, and help-seeking for mental health problems. Data were analyzed with mixed-effects models with group by measurement occasion interactions.
3-year follow-up data was obtained from 149 parents and 118 adolescents, who were aged 16.5 years on average. Between baseline and 3-year follow-up, there was a non-significant reduction in adolescent cases of mental health problems relative to the control group (odds ratios (OR) 0.16-0.17), a non-significant improvement in parental support reported by adolescents with a mental health problem (OR 2.80-4.31), and a non-significant improvement in the quality of support that parents reported providing to their adolescents with a mental health problem (d = 0.38). Secondary outcomes that showed significant improvements relative to the control group were parental knowledge about youth mental health problems (d = 0.31) and adolescent perceptions of general social support from their parents (d = 0.35).
This paper reports on the longest follow-up of Mental Health First Aid training in a controlled trial. Three years after training, participants had maintained their improved knowledge about mental health problems. There were some indications of other positive effects, but the study was underpowered to clearly show benefits to mental health first aid skills and recipients of aid.
ACTRN 12612000390886 , registered retrospectively 5/4/2012, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=347502.
The substitution of non-native metal ions into metalloenzyme active sites is a common strategy for gaining insights into enzymatic structure and function. For some nonheme iron dioxygenases, ...replacement of the Fe(ii) center with a redox-active, divalent transition metal (e.g., Mn, Co, Ni, Cu) gives rise to an enzyme with equal or greater activity than the wild-type enzyme. In this manuscript, we apply this metal-substitution approach to synthetic models of the enzyme cysteine dioxygenase (CDO). CDO is a nonheme iron dioxygenase that initiates the catabolism of l-cysteine by converting this amino acid to the corresponding sulfinic acid. Two mononuclear Co(ii) complexes (3 and 4) have been prepared with the general formula Co
(Tp
)(CysOEt) (R = Ph (3) or Me (4); Tp
= hydrotris(pyrazol-1-yl)borate substituted with R-groups at the 3- and 5-positions, and CysOEt is the anion of l-cysteine ethyl ester). These Co(ii) complexes mimic the active-site structure of substrate-bound CDO and are analogous to functional iron-based CDO models previously reported in the literature. Characterization with X-ray crystallography and/or
H NMR spectroscopy revealed that 3 and 4 possess five-coordinate structures featuring facially-coordinating Tp
and S,N-bidentate CysOEt ligands. The electronic properties of these high-spin (S = 3/2) complexes were interrogated with UV-visible absorption and X-band electron paramagnetic resonance (EPR) spectroscopies. The air-stable nature of complex 3 replicates the inactivity of cobalt-substituted CDO. In contrast, complex 4 reversibly binds O
at reduced temperatures to yield an orange chromophore (4-O
). Spectroscopic (EPR, resonance Raman) and computational (density functional theory, DFT) analyses indicate that 4-O
is a S = 1/2 species featuring a low-spin Co(iii) center bound to an end-on (η
) superoxo ligand. DFT calculations were used to evaluate the energetics of key steps in the reaction mechanism. Collectively, these results have elucidated the role of electronic factors (e.g., spin-state, d-electron count, metal-ligand covalency) in facilitating O
activation and S-dioxygenation in CDO and related models.
A series of mononuclear Co(II) complexes with noninnocent (redox-active) ligands are prepared that exhibit metal–ligand cooperativity during the reversible binding of O2. The complexes have the ...general formula, CoII(L S,N )(TpR2) (R = Me, Ph), where L S,N is a bidentate o-aminothiophenolate and TpR2 is a hydrotris(pyrazol-1-yl)borate scorpionate with R-substituents at the 3- and 5-positions. Exposure to O2 at room temperature results in one-electron oxidation and deprotonation of L S,N . The oxidized derivatives possess substantial “singlet diradical” character arising from antiferromagnetic coupling between an iminothiosemiquinonate (ITSQ•–) ligand radical and a low-spin Co(II) ion. The CoII(TpMe2)(X2ITSQ) complexes, where X = H or tBu, coordinate O2 reversibly at reduced temperatures to provide Co/O2 adducts. The O2 binding reactions closely resemble those previously reported by our group (Kumar et al., J. Am. Chem. Soc. 2019, 141, 10984–10987) for the related complexes CoII(TpMe2)(tBu2SQ) and CoII(TpMe2)(tBu2ISQ), where tBu2(I)SQ represents 4,6-di-tert-butyl-(2-imino)semiquinonate radicals. In each case, the oxygenation reaction proceeds via the addition of O2 to both the cobalt ion and the ligand radical, generating metallocyclic cobalt(III)-alkylperoxo structures. Thermodynamic measurements elucidate the relationship between O2 affinity and redox potentials of the (imino)(thio)semiquinonate radicals, as well as energetic differences between these reactions and conventional metal-based oxygenations. The results highlight the utility and versatility of noninnocent ligands in the design of O2-absorbing compounds.
Mononuclear non-heme iron complexes that serve as structural and functional mimics of the thiol dioxygenases (TDOs), cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO), have been prepared ...and characterized with crystallographic, spectroscopic, kinetic, and computational methods. The high-spin Fe(II) complexes feature the facially coordinating tris(4,5-diphenyl-1-methylimidazol-2-yl)phosphine (Ph2TIP) ligand that replicates the three histidine (3His) triad of the TDO active sites. Further coordination with bidentate l-cysteine ethyl ester (CysOEt) or cysteamine (CysAm) anions yielded five-coordinate (5C) complexes that resemble the substrate-bound forms of CDO and ADO, respectively. Detailed electronic-structure descriptions of the Fe(Ph2TIP)(LS,N)BPh4 complexes, where LS,N = CysOEt (1) or CysAm (2), were generated through a combination of spectroscopic techniques electronic absorption, magnetic circular dichroism (MCD) and density functional theory (DFT). Complexes 1 and 2 decompose in the presence of O2 to yield the corresponding sulfinic acid (RSO2H) products, thereby emulating the reactivity of the TDO enzymes and related complexes. Rate constants and activation parameters for the dioxygenation reactions were measured and interpreted with the aid of DFT calculations for O2-bound intermediates. Treatment of the TDO models with nitric oxide (NO)a well-established surrogate of O2led to a mixture of high-spin and low-spin {FeNO}7 species at low temperature (−70 °C), as indicated by electron paramagnetic resonance (EPR) spectroscopy. At room temperature, these Fe/NO adducts convert to a common species with EPR and infrared (IR) features typical of cationic dinitrosyl iron complexes (DNICs). To complement these results, parallel spectroscopic, computational, and O2/NO reactivity studies were carried out using previously reported TDO models that feature an anionic hydrotris(3-phenyl-5-methyl-pyrazolyl)borate (Ph,MeTp–) ligand. Though the O2 reactivities of the Ph2TIP- and Ph,MeTp-based complexes are quite similar, the supporting ligand perturbs the energies of Fe 3d-based molecular orbitals and modulates Fe–S bond covalency, suggesting possible rationales for the presence of neutral 3His coordination in CDO and ADO.
Aminophenol dioxygenases (APDO) are mononuclear nonheme iron enzymes that utilize dioxygen (O2) to catalyze the conversion of o-aminophenols to 2-picolinic acid derivatives in metabolic pathways. ...This study describes the synthesis and O2 reactivity of two synthetic models of substrate-bound APDO: FeII(TpMe2)(tBu2APH) (1) and FeII(TpMe2)(tBuAPH) (2), where TpMe2 = hydrotris(3,5-dimethylpyrazole-1-yl)borate, tBu2APH = 4,6-di-tert-butyl-2-aminophenolate, and tBuAPH2 = 4-tert-butyl-2-aminophenolate. Both Fe(II) complexes behave as functional APDO mimics, as exposure to O2 results in oxidative CC bond cleavage of the o-aminophenolate ligand. The ring-cleaved products undergo spontaneous cyclization to give substituted 2-picolinic acids, as verified by 1H NMR spectroscopy, mass spectrometry, and X-ray crystallography. Reaction of the APDO models with O2 at low temperature reveals multiple intermediates, which were probed with UV–vis absorption, electron paramagnetic resonance (EPR), Mössbauer (MB), and resonance Raman (rRaman) spectroscopies. The most stable intermediate at −70 °C in THF exhibits multiple isotopically-sensitive features in rRaman samples prepared with 16O2 and 18O2, confirming incorporation of O2-derived atom(s) into its molecular structure. Insights into the geometric structures, electronic properties, and spectroscopic features of the observed intermediates were obtained from density functional theory (DFT) calculations. Although functional APDO models have been previously reported, this is the first time that an oxygenated ligand-based radical has been detected and spectroscopically characterized in the ring-cleaving mechanism of a relevant synthetic system.
Synopsis: Nonheme iron(II) complexes behave as functional models of aminophenol dioxygenases by reacting with O2 to yield oxygenated ring-cleaved products. The mechanism is explored by monitoring the reaction at reduced temperature to observe and trap reactive intermediates. Characterization with multiple spectroscopic techniques revealed that the most stable intermediate contains O2-derived atoms in its molecular structure. Display omitted
•Functional nonheme iron models of aminophenol dioxygenases are prepared and structually characterized.•The models replicate the enzymatic reaction by yielding oxidized ring-cleaved products in the presence of O2.•Intermediates of relevance to enzymatic catalysis are interrogated with multiple spectroscopic techniques.
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