Authors: Thomas Grenier-Larouche, Lydia Coulter Kwee, Yann Deleye...

Hepatic de novo lipogenesis is influenced by the branched-chain α-keto acid dehydrogenase (BCKDH) kinase (BCKDK). Here, we aimed to determine whether circulating levels of the immediate substrates of BCKDH, the branched-chain α-keto acids (BCKAs), and hepatic BCKDK expression are associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD). Eighty metabolites (3 BCKAs, 14 amino acids, 43 acylcarnitines, 20 ceramides) were quantified in plasma from 288 patients with bariatric surgery with severe obesity and scored liver biopsy samples. Metabolite principal component analysis factors, BCKAs, branched-chain amino acids (BCAAs), and the BCKA/BCAA ratio were tested for associations with steatosis grade and presence of nonalcoholic steatohepatitis (NASH). Of all analytes tested, only the Val-derived BCKA, α-keto-isovalerate, and the BCKA/BCAA ratio were associated with both steatosis grade and NASH. Gene expression analysis in liver samples from 2 independent bariatric surgery cohorts showed that hepatic BCKDK mRNA expression correlates with steatosis, ballooning, and levels of the lipogenic transcription factor SREBP1. Experiments in AML12 hepatocytes showed that SREBP1 inhibition lowered BCKDK mRNA expression. These findings demonstrate that higher plasma levels of BCKA and hepatic expression of BCKDK are features of human NAFLD/NASH and identify SREBP1 as a transcriptional regulator of BCKDK.

Topics: Amino Acids, Branched-Chain; Humans; Keto Acids; Non-alcoholic Fatty Liver Disease; Obesity, Morbid; RNA, Messenger

PubMed: 35797133
DOI: 10.1172/jci.insight.159204

Authors: Kiyoto Nishi, Akira Yoshii, Lauren Abell...

Branched-chain amino acid (BCAA) metabolism is linked to glucose homeostasis, but the underlying signaling mechanisms are unclear. We find that gluconeogenesis is reduced in mice deficient of Ppm1k, a positive regulator of BCAA catabolism, which protects against obesity-induced glucose intolerance. Accumulation of branched-chain keto acids (BCKAs) inhibits glucose production in hepatocytes. BCKAs suppress liver mitochondrial pyruvate carrier (MPC) activity and pyruvate-supported respiration. Pyruvate-supported gluconeogenesis is selectively suppressed in Ppm1k-deficient mice and can be restored with pharmacological activation of BCKA catabolism by BT2. Finally, hepatocytes lack branched-chain aminotransferase that alleviates BCKA accumulation via reversible conversion between BCAAs and BCKAs. This renders liver MPC most susceptible to circulating BCKA levels hence a sensor of BCAA catabolism.

Topics: Mice; Animals; Keto Acids; Monocarboxylic Acid Transporters; Gluconeogenesis; Amino Acids, Branched-Chain; Hepatocytes; Pyruvates; Glucose

PubMed: 37310861
DOI: 10.1016/j.celrep.2023.112641

Review

Authors: F E Regnier, J H Law

The evidence for intraspecies chemical communication in insects is reviewed, with emphasis on those studies where known organic compounds have been implicated. These signal-carrying chemicals are known as pheromones. There are two distinct types of pheromones, releasers and primers. Releaser pheromones initiate immediate behavioral responses in insects upon reception, while primer pheromones cause physiological changes in an animal that ultimately result in a behavior response. Chemically identified releaser pheromones are of three basic types: those which cause sexual attraction, alarm behavior, and recruitment. Sex pheromones release the entire repertoire of sexual behavior. Thus a male insect may be attracted to and attempt to copulate with an inanimate object that has sex pheromone on it. It appears that most insects are rather sensitive and selective for the sex pheromone of their species. Insects show far less sensitivity and chemospecificity for alarm pheromones. Alarm selectivity is based more on volatility than on unique structural features. Recruiting pheromones are used primarily in marking trails to food sources. Terrestrial insects lay continuous odor trails, whereas bees and other airborne insects apply the substances at discrete intervals. It appears that a complex pheromone system is used by the queen bee in the control of worker behavior. One well-established component of this system is a fatty acid, 9-ketodecenoic acid, produced by the queen and distributed among the workers. This compound prevents the development of ovaries in the workers and inhibits their queen-rearing activities. In addition, the same compound is used by virgin queen bees as a sex attractant.

Topics: Alcohols; Animal Communication; Animals; Ants; Bees; Bombyx; Chemical Phenomena; Chemistry; Coleoptera; Female; Insecta; Keto Acids; Male; Pheromones; Sex; Species Specificity; Terpenes

PubMed: 4882034
DOI: No ID Found

Authors: Xiaocui Ling, Xiao Liu, Kun Wang...

Cyclic di-GMP (c-di-GMP) is a second messenger that promotes biofilm formation in several bacterial species, but the mechanisms are often unclear. Here, we report that c-di-GMP promotes biofilm formation in mycobacteria in a manner dependent on the nucleoid-associated protein Lsr2. We show that c-di-GMP specifically binds to Lsr2 at a ratio of 1:1. Lsr2 upregulates the expression of HadD, a (3R)-hydroxyacyl-ACP dehydratase, thus promoting the synthesis of keto-mycolic acid and biofilm formation. Thus, Lsr2 acts as a c-di-GMP receptor that links the second messenger's function to lipid synthesis and biofilm formation in mycobacteria.

Topics: Mycolic Acids; Adipogenesis; Mycobacterium; Keto Acids; Biofilms; Cyclic GMP

PubMed: 38267428
DOI: 10.1038/s41467-024-44774-6

Authors: J P GREENSTEIN, V E PRICE

Topics: Asparaginase; Enzymes; Glutaminase; Humans; Keto Acids

PubMed: 18116992
DOI: No ID Found

Authors: Toshio Norikura, Yutaro Sasaki, Akiko Kojima-Yuasa...

α-Keto acids may help prevent malnutrition in patients with chronic kidney disease (CKD), who consume protein-restricted diets, because they serve as amino acid sources without producing nitrogenous waste compounds. However, the physiological roles of α-keto acids, especially those derived from non-essential amino acids, remain unclear. In this study, we examined the effect of glyoxylic acid (GA), an α-keto acid metabolite derived from glycine, on myogenesis in C2C12 cells. Differentiation and mitochondrial biogenesis were used as myogenesis indicators. Treatment with GA for 6 d resulted in an increase in the expression of differentiation markers (myosin heavy chain II and myogenic regulatory factors), mitochondrial biogenesis, and intracellular amounts of amino acids (glycine, serine, and alanine) and their metabolites (citric acid and succinic acid). In addition, GA treatment suppressed the 2.5-µM dexamethasone (Dex)-induced increase in mRNA levels of ubiquitin ligases ( and ), muscle atrophy markers. These results indicate that GA promotes myogenesis, suppresses Dex-induced muscle atrophy, and is metabolized to amino acids in muscle cells. Although further in vivo experiments are needed, GA may be a beneficial nutrient for ameliorating the loss of muscle mass, strength, and function in patients with CKD on a strict dietary protein restriction.

Topics: Humans; Glycine; Cell Differentiation; Keto Acids; Amino Acids; Muscular Atrophy; Muscle Development; Muscle, Skeletal

PubMed: 37049603
DOI: 10.3390/nu15071763

Authors: Lemuel M J Soh, Wai Shun Mak, Paul P Lin...

Keto acid decarboxylase (Kdc) is a key enzyme in producing keto acid derived higher alcohols, like isobutanol. The most active Kdc's are found in mesophiles; the only reported Kdc activity in thermophiles is 2 orders of magnitude less active. Therefore, the thermostability of mesophilic Kdc limits isobutanol production temperature. Here, we report development of a thermostable 2-ketoisovalerate decarboxylase (Kivd) with 10.5-fold increased residual activity after 1h preincubation at 60 °C. Starting with mesophilic Lactococcus lactis Kivd, a library was generated using random mutagenesis and approximately 8,000 independent variants were screened. The top single-mutation variants were recombined. To further improve thermostability, 16 designs built using Rosetta Comparative Modeling were screened and the most active was recombined to form our best variant, LLM4. Compared to wild-type Kivd, a 13 °C increase in melting temperature and over 4-fold increase in half-life at 60 °C were observed. LLM4 will be useful for keto acid derived alcohol production in lignocellulosic thermophiles.

Topics: Butanols; Carboxy-Lyases; Circular Dichroism; Enzyme Stability; Evolution, Molecular; Half-Life; High-Throughput Screening Assays; Keto Acids; Kinetics; Lactococcus lactis; Mutagenesis; Protein Domains; Protein Engineering; Recombinant Proteins; Substrate Specificity; Transition Temperature

PubMed: 28052191
DOI: 10.1021/acssynbio.6b00240

Keto acid decarboxylase and keto acid dehydrogenase activity detected during the biosynthesis of flavor compound 3-methylbutanal by the nondairy adjunct culture Lactococcus lactis ssp. lactis F9.

Authors: Jie Luo, Chenbo Jiang, Liang Zhao...

3-Methylbutanal is one of the primary substances that contribute to the nutty flavor in cheese. Lactococcus strains have been shown to have higher aminotransferase and α-keto acid decarboxylase activities compared with other microbes, indicating that they might form a higher amount of 3-methylbutanal by decarboxylation. Several dairy lactococcal strains have been successfully applied as adjunct cultures to increase the 3-methylbutanal content of cheese. Moreover, compared with dairy cultures, the nondairy lactococci are generally metabolically more diverse with more active AA-converting enzymes. Therefore, it might be appropriate to use nondairy lactococcal strains as adjunct cultures to enrich the 3-methylbutanal content of cheese. This study thereby aimed to select a nondairy Lactococcus strain that is highly productive of 3-methylbutanal, identify its biosynthetic pathway, and apply it to cheese manufacture. Twenty wild nondairy lactococci isolated from 5 kinds of Chinese traditional fermented products were identified using 16S rRNA sequence analysis and were found to belong to Lactococcus lactis ssp. lactis. The nondairy strains were then screened in vitro for their production of 3-methylbutanal and whether they met the criteria to become an adjunct culture for cheese. The L. lactis ssp. lactis F9, isolated from sour bamboo shoot, was selected because of its higher 3-methylbutanal production, suitable autolysis rate, and lower acid production. The enzymes involved in the catabolic pathway of leucine were then evaluated. Both α-keto acid decarboxylase (6.96 μmol/g per minute) and α-keto acid dehydrogenase (30.06 μmol/g per minute) activities were detected in nondairy L. lactis F9. Cheddar cheeses made with different F9 levels were ripened at 13°C and analyzed after 90 d by a combination of instrumental and sensory methods. The results showed that adding nondairy L. lactis F9 significantly increased 3-methylbutanal content and enhanced the nutty flavor of the cheese without impairing its textural properties. Thus, nondairy L. lactis F9 efficiently enhanced the biosynthesis of 3-methylbutanal in vitro and in manufactured cheese.

Topics: Aldehydes; Bacterial Proteins; Carboxy-Lyases; Cheese; Fermentation; Keto Acids; Lactococcus lactis; Oxidoreductases; RNA, Ribosomal, 16S; Taste

PubMed: 30197150
DOI: 10.3168/jds.2018-14760

Authors: Faben A Cruz, Zhiwei Chen, Sarah I Kurtoic...

Herein, we describe a regioselective Rh-catalyzed decarboxylative cross-coupling of β-keto acids and alkynes to access branched γ,δ-unsaturated ketones. Rh-hydride catalysis enables the isomerization of an alkyne to generate a metal-allyl species that can undergo carbon-carbon bond formation. Ketones are generated under mild conditions, without the need for base or activated electrophiles.

Topics: Alkynes; Catalysis; Decarboxylation; Keto Acids; Ketones; Models, Chemical; Rhodium

PubMed: 27043656
DOI: 10.1039/c6cc02522f

Review

Authors: Project Nshimiyimana, Long Liu, Guocheng Du...

α-keto acids are organic compounds that contain an acid group and a ketone group. L-amino acid deaminases are enzymes that catalyze the oxidative deamination of amino acids for the formation of their corresponding α-keto acids and ammonia. α-keto acids are synthesized industrially via chemical processes that are costly and use harsh chemicals. The use of the directed evolution technique, followed by the screening and selection of desirable variants, to evolve enzymes has proven to be an effective way to engineer enzymes with improved performance. This review presents recent studies in which the directed evolution technique was used to evolve enzymes, with an emphasis on L-amino acid deaminases for the whole-cell biocatalysts production of α-keto acids from their corresponding L-amino acids. We discuss and highlight recent cases where the engineered L-amino acid deaminases resulted in an improved production yield of phenylpyruvic acid, α-ketoisocaproate, α-ketoisovaleric acid, α-ketoglutaric acid, α-keto-γ-methylthiobutyric acid, and pyruvate.

Topics: Amidohydrolases; Amino Acids; Ammonia-Lyases; Bacillus subtilis; Biocatalysis; Directed Molecular Evolution; Escherichia coli; Hemiterpenes; Humans; Industrial Microbiology; Keto Acids; Ketoglutaric Acids; Methionine; Protein Engineering; Proteus; Pyruvic Acid

PubMed: 30876377
DOI: 10.1080/21655979.2019.1595990