Short-chain fatty acid derivation

J.J. Kabara and G.V. Haitsma, Aminimides, II, Antimicrobial effect of short chain fatty acid derivatives, J. Am. Oil Chem. Soc. 52 (1975) 444-447. 

After a protein meal, dietary glutamine is a major fuel for the gut, and the products of glutamine metabolism are similar to those seen in the postabsorptive state. The gut also uses dietary aspartate and glutamate, which enter the TCA cycle. Colonocytes (the cells of the colon) also use short-chain fatty acids, derived from bacterial action in the lumen. 

Although fermentation of fiber tends to reduce its effectiveness as a source of fecal bulk, it has other very important benefits. The absorption and metabolism of short-chain fatty acids derived from carbohydrate fermentation provides the route for the recovery of energy from undigested polysaccharides. Butyrate functions as the preferred source of energy for the colonic mucosal cells, whilst propionate and acetate are absorbed and metabolized systemically. There continues to be much debate about the importance of butyrate for the colon. In vitro, butyrate causes differentiation of tumor cells, suppresses cell division, and induces programed cell death (apoptosis). These effects are thought likely to suppress the development of cancer, but it is not yet entirely clear whether they also occur in the intact intestine. Research continues on the importance of butyrate and other short-chain fatty acids for human health. 

All of the other enzymes of the /3-oxidation pathway are located in the mitochondrial matrix. Short-chain fatty acids, as already mentioned, are transported into the matrix as free acids and form the acyl-CoA derivatives there. However, long-chain fatty acyl-CoA derivatives cannot be transported into the matrix directly. These long-chain derivatives must first be converted to acylearnitine derivatives, as shown in Figure 24.9. Carnitine acyltransferase I, located on the outer side of the inner mitochondrial membrane, catalyzes the formation of... 

Histone deacetylases are linked to the pathogenesis of malignancy from a mechanistic perspective. The capacity of HDAC inhibitors (HDACi) to interfere with the enzyme fimction has led to the observed prechnical and clinical activity in cancer therapy. Although the exact mechanism of anti-tumor activity is not fully elucidated, various cellular pathways have been shown to be involved. From the first chnical trials involving HDACi with short chain fatty acids to the newer generation hydroxamic acid derivatives and cychc tetrapeptides, a number of structurally diverse compounds have made the transition from the laboratory to the chnical arena. For purposes of this part of the discussion, HDACi are arbitrarily divided into the hydroxamates and nonhydroxamates. 

The short chain fatty acids include butyrate derivatives Hke phenylbu-tyrate, AN-9 (pivaloyloxymethyl butyrate) and valproate. Unfortimately, these compounds have poor potency and pharmacokinetic properties, including short half-life. Numerous Phase I studies with phenylbutyrate, in various oral and intravenous schedules [118-120] have been performed, with neurological toxicity at higher doses being reported. AN-9 showed initial promise in a Phase I study, where the MTD was not reached [121]. The subsequent Phase II study in nonsmall cell lung cancer in 47 patients resulted in fatigue, nausea and dysgeusia as common toxicities. Three partial responses (PR)... 

In the ruminant mammary tissue, it appears that acetate and /3-hydroxybutyrate contribute almost equally as primers for fatty acid synthesis (Palmquist et al. 1969 Smith and McCarthy 1969 Luick and Kameoka 1966). In nonruminant mammary tissue there is a preference for butyryl-CoA over acetyl-CoA as a primer. This preference increases with the length of the fatty acid being synthesized (Lin and Kumar 1972 Smith and Abraham 1971). The primary source of carbons for elongation is malonyl-CoA synthesized from acetate. The acetate is derived from blood acetate or from catabolism of glucose and is activated to acetyl-CoA by the action of acetyl-CoA synthetase and then converted to malonyl-CoA via the action of acetyl-CoA carboxylase (Moore and Christie, 1978). Acetyl-CoA carboxylase requires biotin to function. While this pathway is the primary source of carbons for synthesis of fatty acids, there also appears to be a nonbiotin pathway for synthesis of fatty acids C4, C6, and C8 in ruminant mammary-tissue (Kumar et al. 1965 McCarthy and Smith 1972). This nonmalonyl pathway for short chain fatty acid synthesis may be a reversal of the /3-oxidation pathway (Lin and Kumar 1972). 

Increased sialyl transferase activity was dose and time dependent, and reversible (8). Maximal activity was obtained by exposing the cells to 5 mM butyrate for 24 h. Following removal of butyrate, the enzyme had a half-life of 7 h and activity reached control levels by 24 h. Of the numerous short chain fatty acids and derivatives tested, only butyrate, pentanoate and propionate were effective (8). 

Short-chain fatty acids fatty acids thought to be derived from aquatic sources (C12-C18) to others (C44-C18) from multi-sources (zooplankton, bacteria, and benthic animal and marsh plants). 

Esters for the selective and sensitive detection of carboxylic acids contain atoms or functional groups for which the detector is specific. As with substances of other types, preferably derivatives containing halogens are used for electron-capture detection. Karmen [151] suggested 2-chloroethyl esters for specific detection with the aid of the alkali FID. They are much less volatile than methyl or ethyl esters, and are therefore interesting for the analysis of short-chain fatty acids. GC separation was carried out on EGA polyester or SE-30. 

The initial step in the metabolism of short-chain fatty acids, w hether In cells of the gut lining or in the liver, is conversion to the coenzyine A derivative. For example, acetate is converted to acetyl coeuzyme A (acetyl CoA). The acetyl Co A formed in the cytoplasm can be used for the synthesis of fatly acids, w hereas that formed In the mitochondria can be used for immediate oxidation. Propioriyl CoA can be metabolized as shown in Figure8.7 in Chapter 8. Butyric acid can enter the mitochondria for conversion to butyryl CoA and oxidation in the pathway of fatty acid oxidation. 

Cycloalkane, cyclo alkene, or branched alkane bearing hetero atoms were introduced at C-13 instead of the ethyl group of EMs A and B by feeding short-chain fatty acid precursors into the fermentation broth of genetically modified Saccharopolyspora erythraea. The cyclopentyl EM B (70) (Fig. 15) obtained and the related derivatives exhibited activity comparable to that of EM B against S. aureus (MIC 70 1.56 1 pg/ml) and E. coli (MIC 70 0.1 1 25 pg/ml) [94, 95]. 

Nonsteroidal antiinflammatory drugs. Pirprofen, naproxen, ibuprofen, and keto-profen can occasionally cause microvesicular steatosis in humans (Bravo et al. 1997 Victorino et al. 1980 Danan et al. 1985 Dutertre et al. 1991). These NSAIDS have a 2-arylpropionate structure, with an asymmetric carbon, and exist as either the S(+)- or the R(—)-enantiomers. Only the S(+)-enantiomer inhibits prostaglandin synthesis, whereas only the R( )-enantiomer is converted into the acyl-CoA derivative. However, both the S(+)-enantiomer and the R( )-enantiomer of ibuprofen inhibit the p-oxidation of medium- and short-chain fatty acids (Freneaux et al. 1990). Pirprofen, tiaprofenic acid, and flurbiprofen also inhibit mitochondrial p-oxidation (Geneve et al. 1987a). 

These electron-capturing esters are popular for the GC analysis of short-chain fatty acids because their use avoids evaporative losses of the esters of the lower acids, but many other acids have also been esterified to these derivatives. Conventional methods have been widely used, but a crown ether method has also been described. 

Phospholipids contribute specific aroma to heated milk, meat and other cooked foods through lipid oxidation derived volatile compounds and interaction with Maillard reaction products. Most of the aroma significant volatiles from soybean lecithin are derived from lipid decomposition and Maillard reaction products including short-chain fatty acids, 2-heptanone, hexanal, and short-chain branched aldehydes formed by Strecker degradation (reactions of a-dicarbonyl compounds with amino acids). The most odor-active volatiles identified from aqueous dispersions of phosphatidylcholine and phos-phatidylethanolamine include fra 5 -4,5-epoxy-c/5-2-decenal, fran5,fran5-2,4-decadienal, hexanal, fra 5, d5, d5 -2,4,7-tridecatrienal (Table 11.9). Upon heating, these phospholipids produced cis- and franj-2-decenal and fra 5-2-undecenal. Besides fatty acid composition, other unknown factors apparently affect the formation of carbonyl compounds from heated phospholipids. 

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