-
The Biochemical Journal May 2023Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these... (Review)
Review
Mitochondrial β-oxidation is the most prominent pathway for fatty acid oxidation but alternative oxidative metabolism exists. Fatty acid ω-oxidation is one of these pathways and forms dicarboxylic acids as products. These dicarboxylic acids are metabolized through peroxisomal β-oxidation representing an alternative pathway, which could potentially limit the toxic effects of fatty acid accumulation. Although dicarboxylic acid metabolism is highly active in liver and kidney, its role in physiology has not been explored in depth. In this review, we summarize the biochemical mechanism of the formation and degradation of dicarboxylic acids through ω- and β-oxidation, respectively. We will discuss the role of dicarboxylic acids in different (patho)physiological states with a particular focus on the role of the intermediates and products generated through peroxisomal β-oxidation. This review is expected to increase the understanding of dicarboxylic acid metabolism and spark future research.
Topics: Microbodies; Fatty Acids; Oxidation-Reduction; Mitochondria; Liver; Dicarboxylic Acids
PubMed: 37140888
DOI: 10.1042/BCJ20230041 -
Molecular and Cellular Biochemistry Sep 1990Dissociation of protein-containing structures by modification of protein amino groups with dicarboxylic acid anhydrides is a mild procedure which, in some cases, offers... (Review)
Review
Dissociation of protein-containing structures by modification of protein amino groups with dicarboxylic acid anhydrides is a mild procedure which, in some cases, offers advantages over treatment with alternative dissociating agents, such as urea, guanidine hydrochloride, detergents, high ionic strength, and extremes of pH. In addition to dissociating multimeric proteins and protein aggregates, dicarboxylic acid anhydrides are effective dissociating agents for membrane-bound proteins and nucleoprotein particles. With most dicarboxylic acid anhydrides reviewed, the introduced reagent residues can be eliminated under moderate acid conditions, which allows the purification of unmodified individual components, and the use of diassembly-reconstitution systems valuable for investigating the structural and functional roles played by the individual components of complex particles. Each reagent can be suitable for a particular purpose, depending on the required specificity of the modification and stability of the modified groups. The stability of the acylated amino groups ranges from the very stable succinylated amino groups to the very labile acylation obtained with dimethylmaleic anhydride. Between these extremes, the stability of the modified amino groups decreases stepwise in the following order: maleic, exo-cis-3,6-endoxo-delta 4-tetrahydrophthalic, citraconic, and 3,4,5,6-tetrahydrophthalic anhydride. With respect to the selectivity of the produced modification, little or no modification of hydroxyamino acid and cysteine residues has been observed with dimethylmaleic, exo-cis-3,6-endoxo-delta 4-tetrahydrophthalic, and 3,4,5,6-tetrahydrophthalic anhydrides. With the other reagents, the extent of modification of hydroxyamino acid residues increases in the order citraconic, maleic and succinic anhydride. Citraconic and maleic anhydrides can produce irreversible modification of cysteine residues, the reactivity of sulfhydryl groups being higher with maleic anhydride.
Topics: Amino Acids; Anhydrides; Animals; Dicarboxylic Acids; Protein Conformation; Substrate Specificity
PubMed: 2280759
DOI: 10.1007/BF00221051 -
Applied Microbiology and Biotechnology Oct 2022The methylotrophic bacterium Methylorubrum extorquens AM1 has the potential to become a platform organism for methanol-driven biotechnology. Its ethylmalonyl-CoA pathway...
The methylotrophic bacterium Methylorubrum extorquens AM1 has the potential to become a platform organism for methanol-driven biotechnology. Its ethylmalonyl-CoA pathway (EMCP) is essential during growth on C1 compounds and harbors several CoA-activated dicarboxylic acids. Those acids could serve as precursor molecules for various polymers. In the past, two dicarboxylic acid products, namely mesaconic acid and 2-methylsuccinic acid, were successfully produced with heterologous thioesterase YciA from Escherichia coli, but the yield was reduced by product reuptake. In our study, we conducted extensive research on the uptake mechanism of those dicarboxylic acid products. By using 2,2-difluorosuccinic acid as a selection agent, we isolated a dicarboxylic acid import mutant. Analysis of the genome of this strain revealed a deletion in gene dctA2, which probably encodes an acid transporter. By testing additional single, double, and triple deletions, we were able to rule out the involvement of the two other DctA transporter homologs and the ketoglutarate transporter KgtP. Uptake of 2-methylsuccinic acid was significantly reduced in dctA2 mutants, while the uptake of mesaconic acid was completely prevented. Moreover, we demonstrated M. extorquens-based synthesis of citramalic acid and a further 1.4-fold increase in product yield using a transport-deficient strain. This work represents an important step towards the development of robust M. extorquens AM1 production strains for dicarboxylic acids. KEY POINTS: • 2,2-Difluorosuccinic acid is used to select for dicarboxylic acid uptake mutations. • Deletion of dctA2 leads to reduction of dicarboxylic acid uptake. • Transporter-deficient strains show improved production of citramalic acid.
Topics: Dicarboxylic Acids; Escherichia coli; Fumarates; Malates; Maleates; Methanol; Methylobacterium extorquens; Polymers; Succinates
PubMed: 36104545
DOI: 10.1007/s00253-022-12161-0 -
The Journal of Physical Chemistry May 1967
Topics: Chemical Phenomena; Chemistry; Dicarboxylic Acids; Fatty Acids; Urea
PubMed: 6045712
DOI: 10.1021/j100865a008 -
Journal of Agricultural and Food... Mar 2024Mid-to-long-chain dicarboxylic acids (DCA, ≥ 6) are organic compounds in which two carboxylic acid functional groups are present at the terminal position of the... (Review)
Review
Mid-to-long-chain dicarboxylic acids (DCA, ≥ 6) are organic compounds in which two carboxylic acid functional groups are present at the terminal position of the carbon chain. These acids find important applications as structural components and intermediates across various industrial sectors, including organic compound synthesis, food production, pharmaceutical development, and agricultural manufacturing. However, conventional petroleum-based DCA production methods cause environmental pollution, making sustainable development challenging. Hence, the demand for eco-friendly processes and renewable raw materials for DCA production is rising. Owing to advances in systems metabolic engineering, new tools from systems biology, synthetic biology, and evolutionary engineering can now be used for the sustainable production of energy-dense biofuels. Here, we explore systems metabolic engineering strategies for DCA synthesis in various chassis via the conversion of different raw materials into mid-to-long-chain DCAs. Subsequently, we discuss the future challenges in this field and propose synthetic biology approaches for the efficient production and successful commercialization of these acids.
Topics: Metabolic Engineering; Dicarboxylic Acids; Acids; Biofuels; Organic Chemicals
PubMed: 38442481
DOI: 10.1021/acs.jafc.4c00002 -
FEMS Microbiology Letters May 2015As C4-dicarboxylic acids could replace C4-petrochemicals, the reductive tricarboxylic acid (TCA) pathway was overexpressed in Pichia pastoris for production of the...
As C4-dicarboxylic acids could replace C4-petrochemicals, the reductive tricarboxylic acid (TCA) pathway was overexpressed in Pichia pastoris for production of the C4-dicarboxylic acids. Three expression cassettes which carried the pyruvate carboxylase gene (pc), the cytoplasmic malate dehydrogenase gene (mdh1) and the retargeted fumarase gene (Tfum) were integrated into the chromosomal DNA of P. pastoris GS115 alone or jointly. Multicopy integrations were screened using quantitative PCR for C4-dicarboxylic acid overaccumulation. The results showed that the highest titer in 96 h of fumaric, malic and succinic acid (0.76, 42.28 and 9.42 g l(-1)) was obtained by co-expression of pc and mdh1 in P. pastoris. This is the first report about multiple genes engineered in P. pastoris for C4-dicarboxylic acid production. The strain Pp-PC-MDH1, moreover, has a significant potential to produce malic acid in aerobic conditions.
Topics: Citric Acid Cycle; Dicarboxylic Acids; Fumarate Hydratase; Fumarates; Genome, Bacterial; Homologous Recombination; Malate Dehydrogenase; Malates; Metabolic Engineering; Methanol; Pichia; Pyruvate Carboxylase
PubMed: 25862576
DOI: 10.1093/femsle/fnv052 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Dec 2022Long-chain dicarboxylic acid (DCA), a building block for synthesizing a variety of high value-added chemicals, has been widely used in agriculture, chemical, and... (Review)
Review
Long-chain dicarboxylic acid (DCA), a building block for synthesizing a variety of high value-added chemicals, has been widely used in agriculture, chemical, and pharmaceutical industries. The global demand for DCA is increasing in recent years. Compared with chemical synthesis which requires harsh conditions and complicated processes, fermentative production of DCA has many unparalleled advantages, such as low cost and mild reaction conditions. In this review, we summarized the chemical and microbial synthesis methods for DCA and the commercialization status of the fermentation process. Moreover, the advances of using molecular and metabolic engineering to create high-yielding strains for efficient production of DCA were highlighted. Furthermore, the challenges remaining in the microbial fermentation process were also discussed. Finally, the perspectives for developing high titer DCA producing strains by synthetic biology were proposed.
Topics: Fermentation; Dicarboxylic Acids; Metabolic Engineering; Technology
PubMed: 36593186
DOI: 10.13345/j.cjb.220133 -
Molecular Pharmaceutics Aug 2022Acid-base multicomponent systems have become a popular choice as a strategy to fine-tune the physicochemical properties of active pharmaceutical ingredients. Current...
Acid-base multicomponent systems have become a popular choice as a strategy to fine-tune the physicochemical properties of active pharmaceutical ingredients. Current prediction tools based on the principles of anticrystal engineering cannot always accurately predict the nature of intermolecular interactions within a multicomponent system. Even small changes in the physicochemical parameters of parent components can result in unexpected outcomes, and many salt, cocrystal, and ionic liquid forms are still being discovered empirically. In this work, we aimed to establish structural consistency in a series of mixtures comprising lidocaine (LID) with decanedioic, undecanedioic, dodecanedioic, and tridecanedioic acids and to explore how length and flexibility of the acid carbon backbone affect the molecular recognition, crystallization, and thermal behavior of the expected binary systems. We found that neat grinding of LID with dicarboxylic acids results in the formation of eutectic phases. The observed eutectic melting points deviated from the ideal eutectic temperatures predicted by the Schroeder van Laar model because of hydrogen bonding between the reacting components within the mixtures. Furthermore, thermal and infrared analysis provided evidence for the possible formation of new phases stemming from partial ionization of the counterions. Besides, the structure of a previously undetermined form I of the tridecanedioic acid was solved by single crystal X-ray diffraction.
Topics: Crystallization; Dicarboxylic Acids; Hydrogen Bonding; Ionic Liquids; Lidocaine
PubMed: 35850530
DOI: 10.1021/acs.molpharmaceut.2c00381 -
Journal of the American Academy of... Dec 1987This review is an update on the literature accumulated over the past 10 years following the original observation that azelaic acid, a naturally occurring and nontoxic C9... (Review)
Review
This review is an update on the literature accumulated over the past 10 years following the original observation that azelaic acid, a naturally occurring and nontoxic C9 dicarboxylic acid, possesses significant biologic properties and a potential as a therapeutic agent. These studies have shown that azelaic acid is a reversible inhibitor of tyrosinase and other oxidoreductases in vitro and that it inhibits mitochondrial respiration. It can also inhibit anaerobic glycolysis. Both in vitro and in vivo it has an antimicrobial effect on both aerobic and anaerobic (Propionibacterium acnes) microorganisms. In tissue culture it exerts a dose- and time-dependent cytotoxic effect on malignant melanocytes, associated with mitochondrial damage and inhibition of deoxyribonucleic acid (DNA) synthesis. Tumoral cell lines not containing tyrosinase are equally affected. Normal cells in culture exposed to the same concentrations of the diacid that are toxic for tumoral cells are in general not damaged. Radioactive azelaic acid has been shown to penetrate tumoral cells at a higher level than normal cells of the corresponding line. Topically applied (a 20% cream), it has been shown to be of therapeutic value in skin disorders of different etiologies. Its beneficial effect on various forms of acne (comedogenic, papulopustular, nodulocystic) has been clearly demonstrated. Particularly important is its action on abnormal melanocytes, which has led to the possibility of obtaining good results on melasma and highly durable therapeutic responses on lentigo maligna. It is also capable of causing regression of cutaneous malignant melanoma, but its role in melanoma therapy remains to be investigated.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Acne Vulgaris; Antineoplastic Agents; Dicarboxylic Acids; Humans; Skin Diseases; Skin Neoplasms
PubMed: 2963038
DOI: 10.1016/s0190-9622(87)70294-1 -
The Journal of Biological Chemistry 2021Fasting induces lipid accumulation in the liver, while the mechanisms by which fasting dysregulates liver fatty acid oxidation are not clear. Fatty acid ω-oxidation is...
Fasting induces lipid accumulation in the liver, while the mechanisms by which fasting dysregulates liver fatty acid oxidation are not clear. Fatty acid ω-oxidation is induced in the fasting state, and administration of dicarboxylic acids to fasting animals decreases plasma ketone bodies. We hypothesized that endogenous dicarboxylic acids might play a role in controlling mitochondrial β-oxidation in fasting animals. A peroxisome proliferator-activated receptor-alpha agonist and an inhibitor for peroxisomal β-oxidation were administered to the fasting rats to investigate the role of dicarboxylic acids in liver fatty acid oxidation and lipid homeostasis. We observed that excessive β-oxidation of endogenous dicarboxylic acids by peroxisomes generated considerable levels of succinate in the liver. Excessive succinate oxidation subsequently increased the mitochondrial NADH/NAD ratio and led to an accumulation of 3-OH-CoA and 2-enoyl-CoA intermediates in the liver. This further induced feedback suppression of mitochondrial β-oxidation and promoted hepatic lipid deposition and steatosis. Specific inhibition of peroxisomal β-oxidation attenuated fasting-induced lipid deposition in the liver by reducing succinate production and enhancing mitochondrial fatty acid oxidation. We conclude that suppression of mitochondrial β-oxidation by oxidation of dicarboxylic acids serves as a mechanism for fasting-induced hepatic lipid accumulation and identifies cross talk between peroxisomal and mitochondrial fatty acid oxidation.
Topics: Animals; Dicarboxylic Acids; Fasting; Ketone Bodies; Lipid Metabolism; Liver; Male; Mitochondria; Oxidation-Reduction; Peroxisomes; Rats; Rats, Sprague-Dawley
PubMed: 33811861
DOI: 10.1016/j.jbc.2021.100622