-
Protein Science : a Publication of the... Aug 2021Aldehyde dehydrogenase 4A1 (ALDH4A1) catalyzes the final steps of both proline and hydroxyproline catabolism. It is a dual substrate enzyme that catalyzes the NAD...
Aldehyde dehydrogenase 4A1 (ALDH4A1) catalyzes the final steps of both proline and hydroxyproline catabolism. It is a dual substrate enzyme that catalyzes the NAD -dependent oxidations of L-glutamate-γ-semialdehyde to L-glutamate (proline metabolism), and 4-hydroxy-L-glutamate-γ-semialdehyde to 4-erythro-hydroxy-L-glutamate (hydroxyproline metabolism). Here we investigated the inhibition of mouse ALDH4A1 by the six stereoisomers of proline and 4-hydroxyproline using steady-state kinetics and X-ray crystallography. Trans-4-hydroxy-L-proline is the strongest of the inhibitors studied, characterized by a competitive inhibition constant of 0.7 mM, followed by L-proline (1.9 mM). The other compounds are very weak inhibitors (approximately 10 mM or greater). Insight into the selectivity for L-stereoisomers was obtained by solving crystal structures of ALDH4A1 complexed with trans-4-hydroxy-L-proline and trans-4-hydroxy-D-proline. The structures suggest that the 10-fold greater preference for the L-stereoisomer is due to a serine residue that hydrogen bonds to the amine group of trans-4-hydroxy-L-proline. In contrast, the amine group of the D-stereoisomer lacks a direct interaction with the enzyme due to a different orientation of the pyrrolidine ring. These results suggest that hydroxyproline catabolism is subject to substrate inhibition by trans-4-hydroxy-L-proline, analogous to the known inhibition of proline catabolism by L-proline. Also, drugs targeting the first enzyme of hydroxyproline catabolism, by elevating the level of trans-4-hydroxy-L-proline, may inadvertently impair proline catabolism by the inhibition of ALDH4A1.
Topics: 1-Pyrroline-5-Carboxylate Dehydrogenase; Animals; Crystallography, X-Ray; Hydroxyproline; Mice; Models, Molecular; Proline; Stereoisomerism
PubMed: 34048122
DOI: 10.1002/pro.4131 -
Biomolecules Oct 2021Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and... (Review)
Review
Cyclic dipeptides, also know as diketopiperazines (DKP), the simplest cyclic forms of peptides widespread in nature, are unsurpassed in their structural and bio-functional diversity. DKPs, especially those containing proline, due to their unique features such as, inter alia, extra-rigid conformation, high resistance to enzyme degradation, increased cell permeability, and expandable ability to bind a diverse of targets with better affinity, have emerged in the last years as biologically pre-validated platforms for the drug discovery. Recent advances have revealed their enormous potential in the development of next-generation theranostics, smart delivery systems, and biomaterials. Here, we present an updated review on the biological and structural profile of these appealing biomolecules, with a particular emphasis on those with anticancer properties, since cancers are the main cause of death all over the world. Additionally, we provide a consideration on supramolecular structuring and synthons, based on the proline-based DKP privileged scaffold, for inspiration in the design of compound libraries in search of ideal ligands, innovative self-assembled nanomaterials, and bio-functional architectures.
Topics: Diketopiperazines; Dipeptides; Drug Discovery; Humans; Neoplasms; Peptides, Cyclic; Proline
PubMed: 34680148
DOI: 10.3390/biom11101515 -
Structure (London, England : 1993) Nov 2023Proline cis/trans isomerization plays an important role in many biological processes but occurs on time scales not accessible to brute-force molecular dynamics (MD)...
Proline cis/trans isomerization plays an important role in many biological processes but occurs on time scales not accessible to brute-force molecular dynamics (MD) simulations. We have designed a new Hamiltonian replica exchange scheme, ω-bias potential replica exchange molecular dynamics (ωBP-REMD), to efficiently and accurately calculate proline cis/trans isomerization free energies. ωBP-REMD is applied to various proline-containing tripeptides and a biologically important proline residue in the N2-domain of the gene-3-protein of phage fd in the wildtype and mutant variants of the protein. Excellent cis/trans transition rates are obtained. Reweighting of the sampled probability distribution along the peptide bond dihedral angle allows construction of the corresponding free-energy profile and calculation of the cis/trans isomerization free energy with high statistical precision. Very good agreement with experimental data is obtained. ωBP-REMD outperforms standard umbrella sampling in terms of convergence and agreement with experiment and strongly reduces perturbation of the local structure near the proline residue.
Topics: Molecular Dynamics Simulation; Proline; Proteins; Peptides
PubMed: 37657438
DOI: 10.1016/j.str.2023.08.008 -
Journal of the American Chemical Society Oct 2022Collagen model peptides (CMPs), composed of proline-(2,4)-hydroxyproline-glycine (POG) repeat units, have been extensively used to study the structure and stability of...
Collagen model peptides (CMPs), composed of proline-(2,4)-hydroxyproline-glycine (POG) repeat units, have been extensively used to study the structure and stability of triple-helical collagen─the dominant structural protein in mammals─at the molecular level. Despite the more than 50-year history of CMPs and numerous studies on the relationship between the composition of single-stranded CMPs and the thermal stability of the assembled triple helices, little attention has been paid to the effects arising from their terminal residues. Here, we show that frame-shifted CMPs, which share POG repeat units but terminate with P, O, or G, form triple helices with vastly different thermal stabilities. A melting temperature difference as high as 16 °C was found for triple helices from 20-mers Ac-OG[POG]-NH and Ac-[POG]PO-NH, and triple helices of the constitutional isomers Ac-[POG]-NH and Ac-[GPO]-NH melt 10 °C apart. A combination of thermal denaturation, circular dichroism and NMR spectroscopic studies, and molecular dynamics simulations revealed that the stability differences originate from the propensity of the peptide termini to preorganize into a polyproline-II helical structure. Our results advise that care must be taken when designing peptide mimics of structural proteins, as subtle changes in the terminal residues can significantly affect their properties. Our findings also provide a general and straightforward tool for tuning the stability of CMPs for applications as synthetic materials and biological probes.
Topics: Amino Acid Sequence; Circular Dichroism; Collagen; Glycine; Hydroxyproline; Peptides; Proline
PubMed: 36179150
DOI: 10.1021/jacs.2c08727 -
Journal of Nanobiotechnology Jun 2022Heavy metals repress tobacco growth and quality, and engineered nanomaterials have been used for sustainable agriculture. However, the underlying mechanism of...
BACKGROUND
Heavy metals repress tobacco growth and quality, and engineered nanomaterials have been used for sustainable agriculture. However, the underlying mechanism of nanoparticle-mediated cadmium (Cd) toxicity in tobacco remains elusive.
RESULTS
Herein, we investigated the effects of FeO and ZnO nanoparticles (NPs) on Cd stress in tobacco cultivar 'Yunyan 87' (Nicotiana tabacum). Cd severely repressed tobacco growth, whereas foliar spraying with FeO and ZnO NPs promoted plant growth, as indicated by enhancing plant height, root length, shoot and root fresh weight under Cd toxicity. Moreover, FeO and ZnO NPs increased, including Zn, K and Mn contents, in the roots and/or leaves and facilitated seedling growth under Cd stress. Metabolomics analysis showed that 150 and 76 metabolites were differentially accumulated in roots and leaves under Cd stress, respectively. These metabolites were significantly enriched in the biosynthesis of amino acids, nicotinate and nicotinamide metabolism, arginine and proline metabolism, and flavone and flavonol biosynthesis. Interestingly, FeO and ZnO NPs restored 50% and 47% in the roots, while they restored 70% and 63% in the leaves to normal levels, thereby facilitating plant growth. Correlation analysis further indicated that these metabolites, including proline, 6-hydroxynicotinic acid, farrerol and quercetin-3-O-sophoroside, were significantly correlated with plant growth.
CONCLUSIONS
These results collectively indicate that metal nanoparticles can serve as plant growth regulators and provide insights into using them for improving crops in heavy metal-contaminated areas.
Topics: Cadmium; Metabolomics; Metal Nanoparticles; Metals, Heavy; Nanoparticles; Plant Leaves; Plant Roots; Proline; Soil Pollutants; Nicotiana; Zinc Oxide
PubMed: 35761340
DOI: 10.1186/s12951-022-01509-3 -
Current Opinion in Chemical Biology Oct 2014The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. The requirements of the native chemical... (Review)
Review
The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. The requirements of the native chemical ligation - an N-terminal cysteine and C-terminal thioesters - have encouraged a search for alternative amide-forming ligation reactions. Among successful alternatives to native chemical ligation, are the α-ketoacid-hydroxylamine ligation with 5-oxaproline and, serine/threonine ligation, and potassium acyltrifluoroborate (KAT) ligation. In addition, the KAT ligation, along with the non-amide forming alkyne-azide ligation, is very useful for synthetic conjugations. All of these recent ligation methods were applied to synthesize different proteins, and have allowed chemists to incorporate unnatural amino acids, or to modify the peptide backbone.
Topics: Alkynes; Amino Acid Sequence; Azides; Models, Molecular; Molecular Sequence Data; Peptides; Proline; Proteins; Serine; Threonine
PubMed: 25299573
DOI: 10.1016/j.cbpa.2014.09.032 -
Chembiochem : a European Journal of... Jun 2019Bicyclic peptides are attractive scaffolds for the design of potent protein binders and new therapeutics. However, peptide bicycles constrained through disulfide bonds...
Bicyclic peptides are attractive scaffolds for the design of potent protein binders and new therapeutics. However, peptide bicycles constrained through disulfide bonds are rarely stable or tolerant to sequence manipulation owing to disulfide isomerization, especially for peptides lacking a regular secondary structure. Herein, we report the discovery and identification of a class of bicyclic peptide scaffolds with ordered but irregular secondary structures. These peptides have a conserved cysteine/proline framework for directing the oxidative folding into a fused bicyclic structure that consists of four irregular turns and a 3 helix (characterized by NMR spectroscopy). This work shows that bicyclic peptides can be stabilized into ordered structures by manipulating both the disulfide bonds and proline-stabilized turns. In turn, this could inspire the design and engineering of multicyclic peptides with new structures and benefit the development of novel protein binders and therapeutics.
Topics: Amino Acid Sequence; Cysteine; Models, Molecular; Peptides; Proline; Protein Structure, Secondary
PubMed: 30770638
DOI: 10.1002/cbic.201800788 -
Chirality Jan 2019Biological enantioenriched chirality is a phenomenon that in living organisms, amino acids and carbohydrates typically have the same absolute configuration. Perhaps one...
Biological enantioenriched chirality is a phenomenon that in living organisms, amino acids and carbohydrates typically have the same absolute configuration. Perhaps one of the earliest attempts to delineate the origins of this phenomenon was a theory known as asymmetric autocatalysis, a reaction in which the structures of the chiral catalyst and the product are the same, and in which the chiral product acts as a chiral catalyst for its own production. In theory, this would mean that small asymmetries in the product will propagate rapidly. However, autocatalysis also relies on the cross-inhibition of chiral states, something that would not likely be possible on primordial Earth. But recently, theories on asymmetric autocatalysis have begun to resurface as more recent findings indicate that other mechanisms exist to stabilize the homochiral states. In this study, I propose an autocatalytic cycle, and using density functional theory, prove that (1) it is plausible on primordial Earth, and (2) it propagates arbitrary asymmetries in proline. Thus, facilitating asymmetry in proline and allowing access to a wide variety of asymmetric proline-catalyzed reactions, including those involved in the synthesis of amino acids and carbohydrates from achiral precursors.
Topics: Catalysis; Earth, Planet; Evolution, Chemical; Glutamic Acid; Proline; Stereoisomerism
PubMed: 30431673
DOI: 10.1002/chir.23032 -
Environmental Science and Pollution... May 2024Phytoremediation has become famous for removing particulate matter (PM) and volatile organic compounds (VOC) in situ. Plants for removing PM and VOC were associated with...
Phytoremediation has become famous for removing particulate matter (PM) and volatile organic compounds (VOC) in situ. Plants for removing PM and VOC were associated with botanical biofilters to attract pollution to the plant. On the other hand, persistent pollution exposure can lower plant health and phytoremediation effectiveness; therefore, improving plant tolerance against stress is necessary. Various elicitors can enhance plant tolerance to certain stressors. This study aims to investigate different elicitors to maintain plant health and improve the use of plants in phytoremediation for PM and VOC pollution. This experiment used Sansevieria trifasciata hort. ex Prain under PM and VOC stress. Exogenous elicitors, such as proline, ornithine, and a commercial product, were applied to the leaf parts before exposure to PM and VOC stress. The initial concentrations of PM, PM, and PM were 300-350, 350-450, and 400-500 µg m, respectively, while the VOC concentration was 2.5-3.0 mg m. The plant was stressed for 7 days. The result indicated that ornithine 10 mM is vital in improving plant tolerance and inducing antioxidant enzymes against PM and VOC, while proline 50 mM and a commercial product could not reduce plant stress. This study suggests that ornithine might be an important metabolite to improve plant tolerance to PM and VOC.
Topics: Proline; Volatile Organic Compounds; Particulate Matter; Ornithine; Biodegradation, Environmental
PubMed: 38693456
DOI: 10.1007/s11356-024-33513-5 -
Construction of Challenging Proline-Proline Junctions via Diselenide-Selenoester Ligation Chemistry.Journal of the American Chemical Society Oct 2018Polyproline sequences are highly abundant in prokaryotic and eukaryotic proteins, where they serve as key components of secondary structure. To date, construction of the...
Polyproline sequences are highly abundant in prokaryotic and eukaryotic proteins, where they serve as key components of secondary structure. To date, construction of the proline-proline motif has not been possible owing to steric congestion at the ligation junction, together with an n → π* electronic interaction that reduces the reactivity of acylated proline residues at the C-terminus of peptides. Here, we harness the enhanced reactivity of prolyl selenoesters and a trans-γ-selenoproline moiety to access the elusive proline-proline junction for the first time through a diselenide-selenoester ligation-deselenization manifold. The efficient nature of this chemistry is highlighted in the high-yielding one-pot assembly of two proline-rich polypeptide targets, submaxillary gland androgen regulated protein 3B and lumbricin-1. This method provides access to the most challenging of ligation junctions, thus enabling the construction of previously intractable peptide and protein targets of increasing structural complexity.
Topics: Amino Acid Motifs; Anti-Bacterial Agents; Humans; Organoselenium Compounds; Peptides; Proline; Salivary Proteins and Peptides; Staphylococcus aureus; Stereoisomerism
PubMed: 30239198
DOI: 10.1021/jacs.8b07877