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DOE OSTI2024

Revealing reaction intermediates in one-carbon elongation by thiamine diphosphate/CoA-dependent enzyme family

2-Hydroxyacyl-CoA lyase/synthase (HACL/S) is a thiamine diphosphate (ThDP)-dependent versatile enzyme originally discovered in the mammalian α-oxidation pathway. HACL/S natively cleaves 2-hydroxyacyl-CoAs and, in its reverse direction, condenses formyl-CoA with aldehydes or ketones. The one-carbon elongation biochemistry based on HACL/S has enabled the use of molecules derived from greenhouse gases as biomanufacturing feedstocks. We investigated several HACL/S family members with high activity in the condensation of formyl-CoA and aldehydes, and distinct chain-length specificities and kinetic parameters. Our analysis revealed the structures of enzymes in complex with acyl-CoA substrates and products, several covalent intermediates, bound ThDP and ADP, as well as the C-terminal active site region. One of these observed states corresponds to the intermediary α–carbanion with hydroxymethyl-CoA covalently attached to ThDP. This research distinguishes HACL/S from related sub-families and identifies key residues involved in substrate binding and catalysis. These findings expand our knowledge of acyloin-condensation biochemistry and offer attractive prospects for biocatalysis using carbon elongation.

2-hydroxyacyl-CoA lyase↗

DOE OSTI2020

Synthesis of α,β‐ and β‐Unsaturated Acids and Hydroxy Acids by Tandem Oxidation, Epoxidation, and Hydrolysis/Hydrogenation of Bioethanol Derivatives

Abstract We report a reaction platform for the synthesis of three different high‐value specialty chemical building blocks starting from bio‐ethanol, which might have an important impact in the implementation of biorefineries. First, oxidative dehydrogenation of ethanol to acetaldehyde generates an aldehyde‐containing stream active for the production of C 4 aldehydes via base‐catalyzed aldol‐condensation. Then, the resulting C 4 adduct is selectively converted into crotonic acid via catalytic aerobic oxidation (62 % yield). Using a sequential epoxidation and hydrogenation of crotonic acid leads to 29 % yield of β‐hydroxy acid (3‐hydroxybutanoic acid). By controlling the pH of the reaction media, it is possible to hydrolyze the oxirane moiety leading to 21 % yield of α,β‐dihydroxy acid (2,3‐dihydroxybutanoic acid). Crotonic acid, 3‐hydroxybutanoic acid, and 2,3‐dihydroxybutanoic acid are archetypal specialty chemicals used in the synthesis of polyvinyl‐co‐unsaturated acids resins, pharmaceutics, and bio‐degradable/ ‐compatible polymers, respectively.

Santhanaraj, Daniel↗

DOE OSTI2023

C−N Coupling through Hydroaminoalkylation on a Single‐Atom Rh Heterogeneous Catalyst

Abstract C−N coupling is significant for the synthesis of fine chemicals toward various applications. Hydroaminoalkylation of olefins is a tandem reaction of C−N coupling involving first the formation of an aldehyde through hydroformylation of an olefin and then the production of amine through reductive amination of the aldehyde. Here we report a stable, supported catalyst of singly dispersed Rh 1 atoms anchored on TiO 2 (P25) nanoparticles designated as Rh 1 /P25. Its high activity for C−N coupling was demonstrated by six hydroaminoalkylations of olefins and amines with selectivity of higher than 90% for producing tertiary amines. The singly dispersed Rh 1 O 4 on P25 exhibit activity and selectivity for hydroaminoalkylation comparable or even higher than some reported molecular catalysts. In contrast to molecular catalysts, the Rh‐based single‐atom Rh heterogeneous catalysis (Rh 1 /P25) can be readily separated from reactants and products, reused for multiple runs of hydroaminoalkylation, and recycled with a low cost.

Li, Yuting↗

DOE OSTI2020

Synthesis of α,β‐ and β‐Unsaturated Acids and Hydroxy Acids by Tandem Oxidation, Epoxidation, and Hydrolysis/Hydrogenation of Bioethanol Derivatives

Santhanaraj, Daniel↗

DOE OSTI2023

C–N Coupling through Hydroaminoalkylation on a Single–Atom Rh Heterogeneous Catalyst

C–N coupling is significant for the synthesis of fine chemicals toward various applications. Hydroaminoalkylation of olefins is a tandem reaction of C–N coupling involving first the formation of an aldehyde through hydroformylation of an olefin and then the production of amine through reductive amination of the aldehyde. Here we report a stable, supported catalyst of singly dispersed Rh 1 atoms anchored on TiO 2 (P25) nanoparticles designated as Rh 1 /P25. Its high activity for C–N coupling was demonstrated by six hydroaminoalkylations of olefins and amines with selectivity of higher than 90% for producing tertiary amines. Furthermore, the singly dispersed Rh 1 O 4 on P25 exhibit activity and selectivity for hydroaminoalkylation comparable or even higher than some reported molecular catalysts. In contrast to molecular catalysts, the Rh-based single-atom Rh heterogeneous catalysis (Rh 1 /P25) can be readily separated from reactants and products, reused for multiple runs of hydroaminoalkylation, and recycled with a low cost.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2023

Reductive amination cascades in cell‐free and resting whole cell formats for valorization of lignin deconstruction products

Abstract The selective introduction of amine groups within deconstruction products of lignin could provide an avenue for valorizing waste biomass while achieving a green synthesis of industrially relevant building blocks from sustainable sources. Here, we built and characterized enzyme cascades that create aldehydes and subsequently primary amines from diverse lignin‐derived carboxylic acids using a carboxylic acid reductase (CAR) and an ω‐transaminase (TA). Unlike previous studies that have paired CAR and TA enzymes, here we examine multiple homologs of each of these enzymes and a broader set of candidate substrates. In addition, we compare the performance of these systems in cell‐free and resting whole‐cell biocatalysis formats using the conversion of vanillate to vanillyl amine as model chemistry. We also demonstrate that resting whole cells can be recycled for multiple batch reactions. We used the knowledge gained from this study to produce several amines from carboxylic acid precursors using one‐pot biocatalytic reactions, several of which we report for the first time. These results expand our knowledge of these industrially relevant enzyme families to new substrates and contexts for environmentally friendly and potentially low‐cost synthesis of diverse aryl aldehydes and amines.

Biotechnology & Applied Microbiology↗

DOE OSTI2023

Citral Hydrogenation over Dilute Alloy Catalysts

Dilute alloy CuPt and NiPt catalysts are studied in the hydrogenation of citral, a model α,β-unsaturated aldehyde. In situ and ex situ characterization is used to demonstrate that the Pt species within these nanoparticles are well dispersed and approach a single atom alloy structure. The distribution of Pt varies between the two host metal systems; under a hydrogen environment, the nanoparticle surface and near-surface region of the NiPt nanoparticles is Pt rich, while the Pt is more uniformly distributed throughout the CuPt nanoparticles. When used for citral hydrogenation reactions, a rate enhancement is observed upon the addition of Pt to the Cu or Ni host catalysts, however this enhancement is determined to be due to the presence of additional metal and not a synergistic effect of the two metals. The Pt structure does, nonetheless, influence the observed selectivity trends. NiPt/SiO 2 catalysts have high selectivity to the unsaturated aldehyde citronellal while the CuPt/SiO 2 catalysts have increased selectivity to unsaturated alcohol products. Further, this increased selectivity is attributed to a combination of hydrogen dissociation over Pt sites and a decrease in size of Cu ensembles due to the presence of Pt, which favors binding and hydrogenation of C=O rather than C=C bonds.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2026

Exploration of Nirmatrelvir Derivatives as Optimized SARS‐CoV‐2 Antivirals

Nirmatrelvir (NMV) is a SARS‐CoV‐2 antiviral component of the approved COVID‐19 therapeutic Paxlovid. It is a reversible covalent inhibitor of SARS‐CoV‐2 main protease (M Pro ) that is effluxed from human cells by P‐glycoprotein (P‐gp). To identify NMV analogs with improved potency and reduced P‐gp efflux, a structure–activity relationship campaign was conducted. Warheads alternative to nitrile for engaging the active site cysteine were tested showing aldehyde and dichloroacetamide with better enzyme inhibition potency. Crystal structure of MPI‐136−M Pro shows its aldehyde warhead forming a thiohemiacetal with active Cys145 of M Pro . Several S4 binders were explored revealing that an O‐to‐S shift at the N ‐terminal amide leads to better enzyme inhibition. By exploring different combinations of S2, S3, and S4 binders, two inhibitors with better enzyme inhibition potency than NMV were found. Crystal structure of MPI‐148, with ( S )‐2‐azaspiro[4,5]decane‐3‐carboxylate as an alternative S2 binder, shows extensive hydrogen‐bond networks for locking the inhibitor in active site, explaining high affinity of NMV analogs. Further characterization of cellular M Pro engagement and antiviral potency against SARS‐CoV‐2 revealed four inhibitors with greater potency than NMV in P‐gp‐expressing cells. Studies with the P‐gp inhibitor CP‐100356 showed that these compounds were less sensitive to P‐gp inhibition than NMV, consistent with reduced P‐gp‐mediated efflux.

Alugubelli, Yugendar R. [Texas A&M Drug Discovery ↗

DOE OSTI2020

Chemical–Switching Strategy for Synthesis and Controlled Release of Norcantharimides from a Biomass–Derived Chemical

Catalytic strategies were developed to synthesize and release chemicals for applications in fine chemicals, such as drugs and polymers, from a biomass-derived chemical, 5-hydroxymethyl furfural (HMF). The combination of the diene and aldehyde functionalities in HMF enabled catalytic production of acetalized HMF derivatives with diol or epoxy reactants to allow reversible synthesis of norcantharimide derivatives upon Diels-Alder reaction with maleimides. Reverse-conversion of the acetal group to an aldehyde yielded mismatches of the molecular orbitals in norcantharimides to trigger retro Diels-Alder reaction at ambient temperatures and released reactants from the coupled molecules under acidic conditions. In conclusion, these strategies provide for the facile synthesis and controlled release of high-value chemicals.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2020

Engineering the cellulolytic extreme thermophile Caldicellulosiruptor bescii to reduce carboxylic acids to alcohols using plant biomass as the energy source

Abstract Caldicellulosiruptor bescii is the most thermophilic cellulolytic organism yet identified (Topt 78 °C). It grows on untreated plant biomass and has an established genetic system thereby making it a promising microbial platform for lignocellulose conversion to bio-products. Here, we investigated the ability of engineered C. bescii to generate alcohols from carboxylic acids. Expression of aldehyde ferredoxin oxidoreductase (aor from Pyrococcus furiosus) and alcohol dehydrogenase (adhA from Thermoanaerobacter sp. X514) enabled C. bescii to generate ethanol from crystalline cellulose and from biomass by reducing the acetate produced by fermentation. Deletion of lactate dehydrogenase in a strain expressing the AOR–Adh pathway increased ethanol production. Engineered strains also converted exogenously supplied organic acids (isobutyrate and n-caproate) to the corresponding alcohol (isobutanol and hexanol) using both crystalline cellulose and switchgrass as sources of reductant for alcohol production. This is the first instance of an acid to alcohol conversion pathway in a cellulolytic microbe.

Biotechnology & Applied Microbiology↗

DOE OSTI2022

Reaction chemistry of ethanol oligomerization to distillate-range molecules using low loading Cu/Mg x AlO y catalysts

We study ethanol oligomerization to higher alcohols and other oxygenates with a 0.3 wt. %Cu/Mg 2.9 AlO catalyst. This reaction involves more than 130 products in a complicated reaction network. The selectivity towards diesel fuel precursor compounds (hereafter ‘DFPC’) increased with conversion until reaching a plateau at an ethanol conversion of ~70 %. Alcohol selectivity was found to follow Schultz-Flory distribution at all studied conversions. Larger sized alcohols then are formed mostly by chain-growth mechanisms via surface reactions of adsorbed oligomers with ethanol-based monomers. Higher esters are formed from alcohols and aldehydes in a series reaction mechanism. Moreover, C 6+ ester and C 4+ ketones selectivities increase as conversion increases. We also found that C 4+ alcohols most likely undergo Guerbet coupling with the studied catalyst to form even higher alcohols once, and that the oxygen of these alcohols is active as a nucleophile, resulting in the selective formation of esters if the starting alcohol is branched. Finally, we performed several cofeed studies varying ethanol-to-H 2 inlet partial pressures, and adding acetaldehyde and ethyl acetate as cofeeds to ethanol at different concentrations. Here, we conclude from these experiments that acetaldehyde concentration controls reaction chemistry, with conditions favoring larger concentrations of the molecule promoting both alcohol coupling and ester formation, and conditions leading to lower concentrations of acetaldehyde resulting in higher alcohol selectivity at the expense of esters and higher aldehydes.

10 SYNTHETIC FUELS↗

DOE OSTI2023

Structure-guided design of direct-acting antivirals that exploit the gem-dimethyl effect and potently inhibit 3CL proteases of severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) and middle east respiratory syndrome coronavirus (MERS-CoV)

The high morbidity and mortality associated with SARS-CoV-2 infection, the etiological agent of COVID-19, has had a major impact on global public health. Significant progress has been made in the development of an array of vaccines and biologics, however, the emergence of SARS-CoV-2 variants and breakthrough infections are an ongoing major concern. Furthermore, there is an existing paucity of small-molecule host and virus-directed therapeutics and prophylactics that can be used to counter the spread of SARS-CoV-2, and any emerging and re-emerging coronaviruses. Here, we describe herein our efforts to address this urgent need by focusing on the structure-guided design of potent broad-spectrum inhibitors of SARS-CoV-2 3C-like protease (3CL pro or Main protease), an enzyme essential for viral replication. The inhibitors exploit the directional effects associated with the presence of a gem-dimethyl group that allow the inhibitors to optimally interact with the S4 subsite of the enzyme. Several compounds were found to potently inhibit SARS-CoV-2 and MERS-CoV 3CL proteases in biochemical and cell-based assays. Specifically, the EC50 values of aldehyde 1c and its corresponding bisulfite adduct 1d against SARS-CoV-2 were found to be 12 and 10 nM, respectively, and their CC50 values were >50 μM. Furthermore, deuteration of these compounds yielded compounds 2c/2d with EC50 values 11 and 12 nM, respectively. Replacement of the aldehyde warhead with a nitrile (CN) or an α-ketoamide warhead or its corresponding bisulfite adduct yielded compounds 1g, 1e and 1f with EC50 values 60, 50 and 70 nM, respectively. High-resolution cocrystal structures have identified the structural determinants associated with the binding of the inhibitors to the active site of the enzyme and, furthermore, have illuminated the mechanism of action of the inhibitors. Overall, the high Safety Index (SI) (SI=CC50/EC50) displayed by these compounds suggests that they are well-suited to conducting further preclinical studies.

3-Chymotrypsin-like protease (3CLpro)↗

DOE OSTI2020

Carbon isotope evidence for the substrates and mechanisms of prebiotic synthesis in the early solar system

Meteorites contain prebiotic, bio-relevant organic compounds including amino acids. Their syntheses could result from diverse sources and mechanisms and provide a window on the conditions and materials present in the early solar system. Here we constrain alanine’s synthetic history in the Murchison meteorite using site-specific 13 C/ 12 C measurements, reported relative to the VPDB standard. The δ 13 C VPDB values of -29 ± 10‰, 142 ± 20‰, and -36 ± 20‰ for the carboxyl, amine-bound, and methyl carbons, respectively, are consistent with Strecker synthesis of interstellar-medium-derived aldehydes, ammonia, and low-δ 13 C nebular or interstellar-medium-derived CN. We report experimentally measured isotope effects associated with Strecker synthesis, and use them to constrain the δ 13 C values of the alanine precursors, which we then use to construct a model that predicts the molecular-average δ 13 C values of 19 other organic compounds of prebiotic significance found in Murchison if they were made by our proposed synthetic network. Finally, most of these predictions agree with previous measurements, suggesting that interstellar-medium-derived aldehydes and nebular and/or pre-solar CN could have served as substrates for synthesis of a wide range of prebiotic compounds in the early solar system.

79 ASTRONOMY AND ASTROPHYSICS↗

DOE OSTI2022

Isotope effects at the origin of life: Fingerprints of the Strecker synthesis

We report strecker synthesis creates α-amino acids from prebiotically plausible substrates (cyanide, ammonia, and aldehydes) and is widely hypothesized to be a key mechanism in the chemistry that led to life on Earth and on other planets. To better constrain the synthetic environments and precursors of abiotic α-amino acids, and to determine unique signatures of abiogenic amino acids, we measured the molecular-averaged and site-specific carbon and nitrogen isotope effects for the Strecker synthesis of alanine. The reaction steps of the Strecker synthesis can be divided into two groups: an initial series of reversible amination and nitrile-addition reactions (‘equilibration’) and a second series of irreversible hydrolysis reactions (‘hydrolysis’). The equilibration of cyanide, acetaldehyde, and ammonia with the intermediate, α-aminopropionitrile (α-APN), has a measured 55.1‰ equilibrium nitrogen isotope effect between the 15 N-rich amine nitrogen in α-aminopropionitrile and the 15 N-poor ammonia and a 20.0‰ equilibrium carbon isotope effect between the 13 C-poor C-2 site in α-aminopropionitrile and the 13 C-rich carbonyl carbon in acetaldehyde. The first irreversible hydrolysis step is inferred to have an up to 10‰ normal carbon fractionation (i.e., faster for 12 C, slower for 13 C) for the whole molecule, but it also has one or more side reactions that deplete the reactive α-APN reservoir by up to 15‰. The second hydrolysis step has a 15.4‰ normal kinetic isotope effect on the amide (C-1) site of alaninamide, which becomes the carboxyl site of alanine. Other α-amino acids will likely experience similar nitrogen isotope fractionations between ammonia and their amine sites, and similar carbon isotope fractionations between the carbonyl carbon in reactant aldehydes or ketones and the intermediate α-aminonitrile, and between cyanide and the carboxyl site. Therefore, these isotope effects allow us to predict the carbon and nitrogen isotopic contents and intramolecular structures of α-amino acids formed by Strecker synthesis based on their substrates’ isotopic compositions, or to infer the isotopic compositions of substrates from which amino acids formed, for example in the case of the amino-acid-rich carbonaceous chondrites. The site-specific C and N isotopic compositions of amino acids formed by Strecker chemistry contrast with those typical of terrestrial biosynthetic amino acids, so these data also provide a means of discriminating between biogenic and abiogenic α-amino acids.

58 GEOSCIENCES↗

DOE OSTI2026

Engineering an aldoxime dehydratase with high activity and isomer tolerance for biosynthesis of an O -protected primary cyanohydrin

O-protected primary cyanohydrins (glycolonitriles) are important building blocks for many difunctionalized compounds and precursors to known bioactive molecules. Their synthesis, however, utilizes toxic cyanide, which raises significant safety concerns for industrial synthesis. Here, in this study, we present a cyanide-free enzymatic synthesis of an o-benzyl protected primary cyanohydrin from an (E)- or (Z)-α-oxygen protected aldoxime using an engineered aldoxime dehydratase enzyme from Bacillus sp. OxB-1 (OxdB). In contrast to many evolved enzymes that tend to “specialize” as their activity increases, we used directed evolution to engineer OxdB for efficient dehydration of both isomers in a mixture of (E)- or (Z)-α-oxygen aldoximes with high activity and substrate loading to achieve near quantitative yield. Using this enzyme, we further demonstrate a cyanide-free chemoenzymatic pathway to an o-protected primary cyanohydrin starting from a readily available aldehyde, where the aldehyde is first condensed with hydroxylamine, followed by dehydration using our evolved enzyme. This pathway was readily scaled up to 1 g scale with high substrate loading, demonstrating its utility in industrial synthesis of these important building block functional groups.

Aldoxime dehydratase↗

DOE OSTI2021

Oxygenate Production from Plasma-Activated Reaction of CO 2 and Ethane

Upgrading ethane with CO 2 as a soft oxidant represents a desirable means of obtaining oxygenated hydrocarbons. This reaction is not thermodynamically feasible under mild conditions and has not been previously achieved as a one-step process. Non-thermal plasma was implemented as an alternative means of supplying energy to overcome activation barriers, leading to the production of alcohols, aldehydes, and acids as well as C 1 -C 5+ hydrocarbons under ambient pressure, with a maximum total oxygenate selectivity of 12%. A plasma chemical kinetic computational model was developed and found to be in good agreement with the experimental trends. Results from this study illustrate the potential to use plasma for the direct synthesis of value-added alcohols, acids, and aldehydes from ethane and CO 2 under mild conditions.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2026

Evaluating the Transport Mechanism for Lignocellulosic Inhibitors in Zymomonas mobilis

The conversion of lignocellulosic biomass to biofuels and bioproducts is limited by small inhibitory molecules generated during the pretreatment process. The diverse compounds within the cell wall hydrolysate including aldehydes, carboxylic acids, phenolics, and alcohols inhibit microbial growth by disrupting microbial membranes. Although Zymomonas mobilis combines high ethanol productivity with hopanoid-rich membranes that confer solvent tolerance, hydrolysate compounds still inhibit microbial growth. One proposed mitigation strategy is to pump these molecules out through active transport processes, reducing direct toxicity. However, if passive permeation rates are high, active transport would create a futile cycle where the exported molecules diffuse back in, creating a net drag on fitness. To investigate this hypothesis, we measure the passive permeation for thirty-three lignocellulose derived compounds using atomistic molecular dynamics simulations with enhanced sampling. Permeability coefficients determined spanned more than eight orders of magnitude driven largely by the balance between hydrophobicity and polarity. Hydrophobic inhibitors such as aromatic acids, aldehydes, and short chain alcohols readily partitioned into the membrane and showed high permeability consistent with rapid passive influx and strong toxicity. Most polar molecules have lower but still appreciable permeation rates, with only the most polar sugars having low permeabilities. By integrating these predictions together with hydrolysate composition information, we find that most of these molecules are so permeable that futile cycles where passive permeation overwhelms efflux is highly likely. These findings provide a predictive framework for strain engineering, highlighting that, for highly permeable inhibitors, reducing extracellular inhibitor concentrations through hydrolysate detoxification, pretreatment optimization, or dilution may be necessary to mitigate futile cycling and improve microbial productivity in industrial biorefineries.

Zymomonas mobilis↗

DOE OSTI2022

Intramolecular C–C Bond Formation Links Anthraquinone and Enediyne Scaffolds in Tiancimycin Biosynthesis

First discovered in 1989, the anthraquinone-fused enediynes are a class of DNA-cleaving bacterial natural products composed of a DNA-intercalating anthraquinone moiety and a 10-membered enediyne warhead. However, until recently, there has been a lack of genetically amenable hosts and sequenced biosynthetic gene clusters available for solving the biosynthetic questions surrounding these molecules. Herein, we have identified and biochemically and structurally characterized TnmK1, a member of the alpha/beta-hydrolase fold superfamily responsible for the C-C bond formation linking the anthraquinone moiety and enediyne core together in tiancimycin (TNM) biosynthesis. In doing so, two intermediates, TNM H and TNM I, in anthraquinone-fused enediyne biosynthesis, containing an unprecedented cryptic C16 aldehyde group, were identified. Here, this aldehyde plays a key role in the TnmK1-catalyzed C-C bond formation via a Michael addition, representing the first example of this chemistry for the alpha/ beta-hydrolase fold superfamily. Additionally, TNM I shows sub-nanomolar cytotoxicity against selected cancer cell lines, indicating a new mechanism of action compared to previously known anthraquinone-fused enediynes. Together, the findings from this study are expected to impact enzymology, natural product biosynthesis, and future efforts at enediyne discovery and drug development.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗