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An ongoing challenge in chemical research is to design catalysts that select the outcomes of the reactions of complex molecules. Chemists rely on organocatalysts or transition metal catalysts to control stereoselectivity, regioselectivity and periselectivity (selectivity among possible pericyclic reactions). Nature achieves these types of selectivity with a variety of enzymes such as the recently discovered pericyclases-a family of enzymes that catalyse pericyclic reactions1. Most characterized enzymatic pericyclic reactions have been cycloadditions, and it has been difficult to rationalize how the observed selectivities are achieved2-13. Here we report the discovery of two homologous groups of pericyclases that catalyse distinct reactions: one group catalyses an Alder-ene reaction that was, to our knowledge, previously unknown in biology; the second catalyses a stereoselective hetero-Diels-Alder reaction. Guided by computational studies, we have rationalized the observed differences in reactivities and designed mutant enzymes that reverse periselectivities from Alder-ene to hetero-Diels-Alder and vice versa. A combination of in vitro biochemical characterizations, computational studies, enzyme co-crystal structures, and mutational studies illustrate how high regioselectivity and periselectivity are achieved in nearly identical active sites.
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Biocatálise , Reação de Cicloadição , Enzimas/metabolismo , Aspergillus/enzimologia , Aspergillus/genética , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Domínio Catalítico , Enzimas/genética , Modelos MolecularesRESUMO
BACKGROUND: The Global Evidence, Local Adaptation (GELA) project aims to maximise the impact of research on poverty-related diseases by increasing researchers' and decision-makers' capacity to use global research to develop locally relevant guidelines for newborn and child health in Malawi, Nigeria and South Africa. To facilitate ongoing collaboration with stakeholders, we adopted an Integrated Knowledge Translation (IKT) approach within GELA. Given limited research on IKT in African settings, we documented our team's IKT capacity and skills, and process and experiences with developing and implementing IKT in these countries. METHODS: Six IKT champions and a coordinator formed the GELA IKT Working Group. We gathered data on our baseline IKT competencies and processes within GELA, and opportunities, challenges and lessons learned, from April 2022 to March 2023 (Year 1). Data was collected from five two-hour Working Group meetings (notes, presentation slides and video recordings); [2] process documents (flowcharts and templates); and [3] an open-ended questionnaire. Data was analysed using a thematic analysis approach. RESULTS: Three overarching themes were identified: [1] IKT approach applied within GELA [2], the capacity and motivations of IKT champions, and [3] the experiences with applying the GELA IKT approach in the three countries. IKT champions and country teams adopted an iterative approach to carry out a comprehensive mapping of stakeholders, determine stakeholders' level of interest in and influence on GELA using the Power-Interest Matrix, and identify realistic indicators for monitoring the country-specific strategies. IKT champions displayed varying capacities, strong motivation, and they engaged in skills development activities. Country teams leveraged existing relationships with their National Ministries of Health to drive responses and participation by other stakeholders, and adopted variable communication modes (e.g. email, phone calls, social media) for optimal engagement. Flexibility in managing competing interests and priorities ensured optimal participation by stakeholders, although the time and resources required by IKT champions were frequently underestimated. CONCLUSIONS: The intentional, systematic, and contextualized IKT approach carried out in the three African countries within GELA, provides important insights for enhancing the implementation, feasibility and effectiveness of other IKT initiatives in Africa and similar low- and middle-income country (LMIC) settings.
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Pesquisa Translacional Biomédica , Humanos , África do Sul , Malaui , Nigéria , Pesquisa Translacional Biomédica/organização & administração , Recém-Nascido , Fortalecimento InstitucionalRESUMO
BACKGROUND: Almost no research has been published reporting on evaluations of the effectiveness of psychological interventions for people with severe to profound intellectual disabilities and depression. This paper describes the development and initial feasibility testing of an adapted Behavioural Activation therapy (BeatIt2) for this population. METHOD: Phase 1 of the study examined participant recruitment and willingness to be randomised in the context of a planned Randomised Controlled Trial (RCT). Phase 2 examined the feasibility of delivering the intervention. RESULTS: Twenty adults with a severe or profound intellectual disability and clinically significant depression were recruited to Phase 1 of the study. In Phase 2, there was 100% participant retention for those recruited to the study at 6-month follow-up. The BeatIt2 therapy was reported to be acceptable for participants. CONCLUSION: COVID disruption meant that it was not possible to complete the planned feasibility RCT. The positive findings suggest that additional evaluation of BeatIt2 is warranted.
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Depressão , Deficiência Intelectual , Adulto , Humanos , Depressão/terapia , Deficiência Intelectual/psicologia , Estudos de Viabilidade , Terapia ComportamentalRESUMO
Stereoselective synthesis of cis-decalin structures using [4 + 2] cycloaddition is challenging. We explored the biosynthetic pathway of the fungal natural product fischerin (1) to identify a new pericyclase FinI that can catalyze such a reaction. The cocrystal structure of FinI, a predicted O-methyltransferase, with the product and SAM provides insight into cis-decalin formation in nature.
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Produtos Biológicos , Biocatálise , Metiltransferases , CatáliseRESUMO
An ambimodal transition state (TS) that leads to formation of four different pericyclic reaction products ([4 + 6]-, [2 + 8]-, [8 + 2]-, and [6 + 4]-cycloadducts) without any intervening minima has been designed and explored with DFT computations and quasiclassical molecular dynamics. Direct dynamics simulations propagated from the ambimodal TS show the evolution of trajectories to give the four cycloadducts. The topography of the PES is a key factor in product selectivity. A good correlation is observed between geometrical resemblance of the products to the ambimodal TS (measured by the RMSD) and the ratio of products formed in the dynamics simulations.
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In nature and synthetic chemistry, stereoselective [2 + 1] cyclopropanation is the most prevalent strategy for the synthesis of chiral cyclopropanes, a class of key pharmacophores in pharmaceuticals and bioactive natural products. One of the most extensively studied reactions in the organic chemist's arsenal, stereoselective [2 + 1] cyclopropanation, largely relies on the use of stereodefined olefins, which can require elaborate laboratory synthesis or tedious separation to ensure high stereoselectivity. Here, we report engineered hemoproteins derived from a bacterial cytochrome P450 that catalyze the synthesis of chiral 1,2,3-polysubstituted cyclopropanes, regardless of the stereopurity of the olefin substrates used. Cytochrome P450BM3 variant P411-INC-5185 exclusively converts (Z)-enol acetates to enantio- and diastereoenriched cyclopropanes and in the model reaction delivers a leftover (E)-enol acetate with 98% stereopurity, using whole Escherichia coli cells. P411-INC-5185 was further engineered with a single mutation to enable the biotransformation of (E)-enol acetates to α-branched ketones with high levels of enantioselectivity while simultaneously catalyzing the cyclopropanation of (Z)-enol acetates with excellent activities and selectivities. We conducted docking studies and molecular dynamics simulations to understand how active-site residues distinguish between the substrate isomers and enable the enzyme to perform these distinct transformations with such high selectivities. Computational studies suggest the observed enantio- and diastereoselectivities are achieved through a stepwise pathway. These biotransformations streamline the synthesis of chiral 1,2,3-polysubstituted cyclopropanes from readily available mixtures of (Z/E)-olefins, adding a new dimension to classical cyclopropanation methods.
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Ciclopropanos , Sistema Enzimático do Citocromo P-450 , Ciclopropanos/química , Estereoisomerismo , Sistema Enzimático do Citocromo P-450/metabolismo , Álcoois , Acetatos , Alcenos/químicaRESUMO
We report biosynthetic pathways that can synthesize and transform conjugated octaenes and nonaenes to complex natural products. The biosynthesis of (-)-PF1018 involves an enzyme PfB that can control the regio-, stereo-, and periselectivity of multiple reactions starting from a conjugated octaene. Using PfB as a lead, we discovered a homologous enzyme, BruB, that facilitates diene isomerization, tandem 8π-6π-electrocyclization, and a 1,2-divinylcyclobutane Cope rearrangement to generate a new-to-nature compound.
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Produtos Biológicos , Produtos Biológicos/metabolismo , Isomerismo , Polienos , CiclizaçãoRESUMO
BACKGROUND: No previous studies have reported predictors and moderators of outcome of psychological therapies for depression experienced by adults with intellectual disabilities (IDs). We investigated baseline variables as outcome predictors and moderators based on a randomised controlled trial where behavioural activation was compared with guided self-help. METHODS: This study was an exploratory secondary data analysis of data collected during a randomised clinical trial. Participants (n = 161) were randomised to behavioural activation or guided self-help and followed up for 12 months. Pre-treatment variables were included if they have previously been shown to be associated with an increased risk of having depression in adults with IDs or have been reported as a potential predictor or moderator of outcome of treatment for depression with psychological therapies. The primary outcome measure, the Glasgow Depression Scale for Adults with Learning Disabilities (GDS-LD), was used as the dependant variable in mixed effects regression analyses testing for predictors and moderators of outcome, with baseline GDS-LD, treatment group, study centre and antidepressant use as fixed effects, and therapist as a random effect. RESULTS: Higher baseline anxiety (mean difference in outcome associated with a 1 point increase in anxiety 0.164, 95% confidence interval [CI] 0.031, 0.297; P = 0.016), lower performance intelligence quotient (IQ) (mean difference in outcome associated with a 1 point increase in IQ 0.145, 95% CI 0.009, 0.280; P = 0.037) and hearing impairment (mean difference 3.449, 95% CI 0.466, 6.432; P = 0.024) were predictors of poorer outcomes, whilst greater severity of depressive symptoms at baseline (mean difference in outcome associated with 1 point increase in depression -0.160, 95% CI -0.806, -0.414; P < 0.001), higher expectation of change (mean difference in outcome associated with a 1 point increase in expectation of change -1.013, 95% CI -1.711, -0.314; p 0.005) and greater percentage of therapy sessions attended (mean difference in outcome with 1 point increase in percentage of sessions attended -0.058, 95% CI -0.099, -0.016; P = 0.007) were predictors of more positive outcomes for treatment after adjusting for randomised group allocation. The final model included severity of depressive and anxiety symptoms, lower WASI performance IQ subscale, hearing impairment, higher expectation of change and percentage of therapy sessions attended and explained 35.3% of the variance in the total GDS-LD score at 12 months (R2 = 0.353, F4, 128 = 17.24, P < 0.001). There is no evidence that baseline variables had a moderating effect on outcome for treatment with behavioural activation or guided self-help. CONCLUSIONS: Our results suggest that baseline variables may be useful predictors of outcomes of psychological therapies for adults with IDs. Further research is required to examine the value of these potential predictors. However, our findings suggest that therapists consider how baseline variables may enable them to tailor their therapeutic approach when using psychological therapies to treat depression experienced by adults with IDs.
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Depressão , Deficiência Intelectual , Adulto , Humanos , Depressão/terapia , Deficiência Intelectual/terapia , Deficiência Intelectual/psicologia , Terapia Comportamental/métodos , Ansiedade , Comportamentos Relacionados com a SaúdeRESUMO
Here we report a computation-driven chemoenzymatic synthesis and biosynthesis of the natural product deoxyakanthomycin, an atropisomeric pyridone natural product that features a 7-membered carbocycle with five stereocenters, one of which a quaternary center. The one-step synthesis from a biosynthetic precursor is based on computational analysis that predicted a σ-bridged cation mediated cyclization mechanism to form deoxyakanthomycin. The σ-bridged cation rationalizes the observed substrate-controlled selectivity; diastereoselectivity arises from attack of water anti to the σ-bridging, as is generally found for σ-bridged cations. Our studies also reveal a unifying biosynthetic strategy for 2-pyridone natural products that derive from a common o-quinone methide to create diverse structures.
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Produtos Biológicos , Piridonas , Produtos Biológicos/química , Cátions , CiclizaçãoRESUMO
We present a measurement of the hydrogen 2S_{1/2}-8D_{5/2} transition performed with a cryogenic atomic beam. The measured resonance frequency is ν=770649561570.9(2.0) kHz, which corresponds to a relative uncertainty of 2.6×10^{-12}. Combining our result with the most recent measurement of the 1S-2S transition, we find a proton radius of r_{p}=0.8584(51) fm and a Rydberg constant of R_{∞}=10973731.568332(52) m^{-1}. This result has a combined 3.1σ disagreement with the Committee on Data for Science and Technology (CODATA) 2018 recommended value.
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INTRODUCTION: Serological methods provide useful metrics to estimate age-specific period prevalence in settings of low malaria transmission; however, evidence on the use of seropositivity as an endpoint remains scarce in studies to evaluate combinations of malaria control measures, especially in children. This study aims to evaluate the immediate effects of a targeted mass drug administration campaign (tMDA) in Haiti by using serological markers. METHODS: The tMDA was implemented in September-October 2018 using sulfadoxine-pyrimethamine and single low-dose primaquine. A natural quasi-experimental study was designed, using a pretest and posttest in a cohort of 754 randomly selected school children, among which 23% reported having received tMDA. Five antigens were selected as outcomes (MSP1-19, AMA-1, Etramp5 antigen 1, HSP40, and GLURP-R0). Posttest was conducted 2-6 weeks after the intervention. RESULTS: At baseline, there was no statistical difference in seroprevalence between the groups of children that were or were not exposed during the posttest. A lower seroprevalence was observed for markers informative of recent exposure (Etramp5 antigen 1, HSP40, and GLURP-R0). Exposure to tMDA was significantly associated with a 50% reduction in the odds of seropositivity for Etramp5 antigen 1 and a 21% reduction in the odds of seropositivity for MSP119. CONCLUSION: Serological markers can be used to evaluate the effects of interventions against malaria on the risk of infection in settings of low transmission. Antibody responses against Etramp5 antigen 1 in Haitian children were reduced in the 2-6 weeks following a tMDA campaign, confirming its usefulness as a short-term marker in child populations.
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Malária Falciparum , Malária , Anticorpos Antiprotozoários , Criança , Combinação de Medicamentos , Haiti/epidemiologia , Humanos , Malária/tratamento farmacológico , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Preparações Farmacêuticas , Plasmodium falciparum , Estudos SoroepidemiológicosRESUMO
Psychoactive natural products play an integral role in the modern world. The tremendous structural complexity displayed by such molecules confers diverse biological activities of significant medicinal value and sociocultural impact. Accordingly, in the last two centuries, immense effort has been devoted towards establishing how plants, animals, and fungi synthesize complex natural products from simple metabolic precursors. The recent explosion of genomics data and molecular biology tools has enabled the identification of genes encoding proteins that catalyze individual biosynthetic steps. Once fully elucidated, the "biosynthetic pathways" are often comparable to organic syntheses in elegance and yield. Additionally, the discovery of biosynthetic enzymes provides powerful catalysts which may be repurposed for synthetic biology applications, or implemented with chemoenzymatic synthetic approaches. In this review, we discuss the progress that has been made toward biosynthetic pathway elucidation amongst four classes of psychoactive natural products: hallucinogens, stimulants, cannabinoids, and opioids. Compounds of diverse biosynthetic origin - terpene, amino acid, polyketide - are identified, and notable mechanisms of key scaffold transforming steps are highlighted. We also provide a description of subsequent applications of the biosynthetic machinery, with an emphasis placed on the synthetic biology and metabolic engineering strategies enabling heterologous production.
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Produtos Biológicos/metabolismo , Psicotrópicos/metabolismo , Produtos Biológicos/química , Estrutura Molecular , Psicotrópicos/químicaRESUMO
OBJECTIVES: We aimed to determine whether women with HIV (WWH) and cervical cancer were more likely to experience cancer-related death and to be diagnosed with cervical cancer at a younger age and in more advanced stages. MATERIALS AND METHODS: This is a retrospective cohort study of all women diagnosed with cervical cancer in South Carolina from 1998 to 2018. Deidentified data were obtained from 2 statewide databases. A survival analysis was performed to evaluate differences in cancer survival between women with and without HIV. Wilcoxon rank sum test was used to determine differences in the median age at cancer diagnosis. χ2 test was used to assess differences in cancer stage according to HIV status. RESULTS: Four thousand three hundred fourteen women were diagnosed with cervical cancer, and 53 (1.2%) had HIV infection. Survival time in months was similar between WWH and HIV-negative women (86 months [interquartile range {IQR} = 32-146] and 62 months [IQR = 18-153], p = .37; log-rank p = .26). Compared with HIV-negative women, WWH were less likely to experience cervical cancer-related death (36% vs. 19%, p = .005). Women with HIV were diagnosed with cervical cancer at a younger age (44 [IQR = 37-54] vs. 49 [IQR = 39-61], p = .02). Cervical cancer stage was similar at diagnosis between groups (tumor node metastasis stage, p = .97, and Surveillance, Epidemiology, and End Results summary stage, p = .41). CONCLUSIONS: Women with HIV were younger at diagnosis than HIV-negative women, but they were no more likely to die from or have more advanced cervical cancer. Women with HIV were not more likely to develop cervical cancer before the age of 21 years and earlier screening is likely unnecessary.
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Infecções por HIV , Neoplasias do Colo do Útero , Adulto , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Programas de Rastreamento , Estudos Retrospectivos , South Carolina/epidemiologia , Neoplasias do Colo do Útero/diagnóstico , Adulto JovemRESUMO
The cycloadditions of cyclopentadiene and cycloheptatriene with tropone are some of the earliest published examples of [6+4] cycloaddition reactions. We report quantum mechanical studies (ωB97X-D and DLPNO-CCSD(T)) of transition structures and products of these reactions, as well as quasi-classical molecular dynamics simulations of reaction trajectories. The study reveals that these cycloadditions involve ambimodal transition states resulting in a web of products by pericyclic interconversion pathways. Combined with these studies, calculations of simple parent systems and a thorough meta-analysis of literature examples reveal the general concept that all endo-[6+4] cycloadditions are ambimodal.
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Medium-ring lactones are synthetically challenging due to unfavorable energetics involved in cyclization. We have discovered a thioesterase enzyme DcsB, from the decarestrictine C1 (1) biosynthetic pathway, that efficiently performs medium-ring lactonizations. DcsB shows broad substrate promiscuity toward linear substrates that vary in lengths and substituents, and is a potential biocatalyst for lactonization. X-ray crystal structure and computational analyses provide insights into the molecular basis of catalysis.
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Lactonas/síntese química , Tioléster Hidrolases/química , Beauveria/enzimologia , Beauveria/genética , Biocatálise , Cristalografia por Raios X , Ciclização , Esterificação , Proteínas Fúngicas/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Lactonas/metabolismo , Simulação de Acoplamento Molecular , Família Multigênica , Ligação Proteica , Especificidade por Substrato , Tioléster Hidrolases/genética , Tioléster Hidrolases/metabolismoRESUMO
Computational studies with ωB97X-D density functional theory of the mechanisms of the steps in Trauner's biomimetic synthesis of preuisolactone A have elaborated and refined mechanisms of several unique processes. An ambimodal transition state has been identified for the cycloaddition between an o-quinone and a hydroxy-o-quinone; this leads to both (5 + 2) (with H shift) and (4 + 2) cycloaddition products, which can in principle interconvert via α-ketol rearrangements. The origins of periselectivity of this ambimodal cycloaddition have been investigated computationally with molecular dynamics simulations and tested further by an experimental study. In the presence of bicarbonate ions, the deprotonated hydroxy-o-quinone leads to only the (5 + 2) cycloaddition adduct. A new mechanism for a benzilic acid rearrangement resulting in ring contraction is proposed.
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Lactonas/síntese química , Sesquiterpenos/síntese química , Bicarbonatos/química , Biomimética/métodos , Reação de Cicloadição , Hidroquinonas/química , Lactonas/química , Quinonas/química , Sesquiterpenos/químicaRESUMO
Hirsutellones are fungal natural products containing a macrocyclic para-cyclophane connected to a decahydrofluorene ring system. We have elucidated the biosynthetic pathway for pyrrocidine B (3) and GKK1032 A2 (4). Two small hypothetical proteins, an oxidoreductase and a lipocalin-like protein, function cooperatively in the oxidative cyclization of the cyclophane, while an additional hypothetical protein in the pyrrocidine pathway catalyzes the exo-specific cycloaddition to form the cis-fused decahydrofluorene.
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Produtos Biológicos/metabolismo , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Fungos/química , Compostos Heterocíclicos de 4 ou mais Anéis/metabolismo , Pirrolidinonas/metabolismo , Acremonium/química , Acremonium/metabolismo , Produtos Biológicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Catálise , Reação de Cicloadição , Fungos/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/química , Hypocreales/química , Hypocreales/metabolismo , Conformação Molecular , Oxirredução , Oxirredutases/metabolismo , Pirrolidinonas/química , EstereoisomerismoRESUMO
The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.
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Sesquiterpenos/química , Tropolona/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Reação de Cicloadição , Teoria da Densidade Funcional , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Conformação Molecular , Sesquiterpenos Monocíclicos/síntese química , Sesquiterpenos Monocíclicos/química , Sesquiterpenos/síntese química , Estereoisomerismo , Tropolona/análogos & derivados , Tropolona/síntese químicaRESUMO
AIMS: Recessive variants in CAPN3 gene are the cause of the commonest form of autosomal recessive limb girdle muscle dystrophy. However, two distinct in-frame deletions in CAPN3 (NM_000070.3:c.643_663del21 and c.598_621del15) and more recently, Gly445Arg and Arg572Pro substitutions have been linked to autosomal dominant (AD) forms of calpainopathy. We report 21 affected individuals from seven unrelated families presenting with an autosomal dominant form of muscular dystrophy associated with five different heterozygous missense variants in CAPN. METHODS: We have used massively parallel gene sequencing (MPS) to determine the genetic basis of a dominant form of limb girdle muscular dystrophy in affected individuals from seven unrelated families. RESULTS: The c.700G> A, [p.(Gly234Arg)], c.1327T> C [p.(Ser443Pro], c.1333G> A [p.(Gly445Arg)], c.1661A> C [p.(Tyr554Ser)] and c.1706T> C [p.(Phe569Ser)] CAPN3 variants were identified. Affected individuals presented in young adulthood with progressive proximal and axial weakness, waddling walking and scapular winging or with isolated hyperCKaemia. Muscle imaging showed fatty replacement of paraspinal muscles, variable degrees of involvement of the gluteal muscles, and the posterior compartment of the thigh and minor changes at the mid-leg level. Muscle biopsies revealed mild myopathic changes. Western blot analysis revealed a clear reduction in calpain 3 in skeletal muscle relative to controls. Protein modelling of these variants on the predicted structure of calpain 3 revealed that all variants are located in proximity to the calmodulin-binding site and are predicted to interfere with proteolytic activation. CONCLUSIONS: We expand the genotypic spectrum of CAPN3-associated muscular dystrophy due to autosomal dominant missense variants.
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Calpaína/genética , Predisposição Genética para Doença/genética , Proteínas Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Adolescente , Adulto , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Análise de Sequência de DNA , Adulto JovemRESUMO
High-quality optical resonant cavities require low optical loss, typically on the scale of parts per million. However, unintended micron-scale contaminants on the resonator mirrors that absorb the light circulating in the cavity can deform the surface thermoelastically and thus increase losses by scattering light out of the resonant mode. The point absorber effect is a limiting factor in some high-power cavity experiments, for example, the Advanced LIGO gravitational-wave detector. In this Letter, we present a general approach to the point absorber effect from first principles and simulate its contribution to the increased scattering. The achievable circulating power in current and future gravitational-wave detectors is calculated statistically given different point absorber configurations. Our formulation is further confirmed experimentally in comparison with the scattered power in the arm cavity of Advanced LIGO measured by in situ photodiodes. The understanding presented here provides an important tool in the global effort to design future gravitational-wave detectors that support high optical power and thus reduce quantum noise.