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Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
ADI, together with ornithine transcarbamylase (OTC, EC 2.1.3.3) and carbamate kinase (CK, EC 2.7.2.2), belongs to the arginine deiminase pathway (ADI pathway), which is used by many l-ARG-dependent microorganisms to catabolize the amino acid-generating ATP. It has been identified, purified, and characterized in bacteria, archaea and some anaerobic eukaryotes (Horn, 1933; Knodler et al., 1994, 1995; Leopoldini et al., 2009), but there is no evidence of its existence in higher eukaryotes. It was demonstrated that ADI only possesses anti-tumour activity in ASS1 deficient tumours, being ineffective when ASS1 is restored (Ensor et al., 2002; Qiu et al., 2014). Further evidence suggests that ADI mediates the inhibition of tumour growth not only by exhausting the supplies of l-ARG, but also by its anti-angiogenic activity via suppression of NO generation (Beloussow et al., 2002; Park et al., 2003; Yoon et al., 2007).
Giardia lamblia
Published in Dongyou Liu, Laboratory Models for Foodborne Infections, 2017
Steven M. Singer, Jenny G. Maloney, Camila H. Coelho
The relationship between Giardia and arginine within the host is of interest because the parasite consumes arginine as an energy source, which could have important implications for immune function and parasite survival during infection. Giardia consumes arginine through a three-step enzymatic pathway that involves arginine deiminase (ADI), ornithine carbamoyltransferase (OCT), and carbamate kinase (CK) with ATP generated as an end product.145 This pathway also serves as a means by which Giardia could reduce arginine availability in the host and limit its conversion to nitric oxide (NO). In fact, arginine is the sole amino acid substrate for NO production by the enzyme nitric oxide synthase (NOS), making it a limiting factor for NO production.146
Intestinal luminal putrescine is produced by collective biosynthetic pathways of the commensal microbiome
Published in Gut Microbes, 2019
Atsuo Nakamura, Takushi Ooga, Mitsuharu Matsumoto
The main pathways by which ornithine is produced from arginine are the arginase or arginine deiminase pathways. The arginine deiminase pathway, which is the most widespread anaerobic route for arginine degradation, is common in intestinal commensal bacteria such as Clostridium, Enterococcus, Lactococcus, Streptococcus, and Lactobacillus.34–38 These genera were detected in the rat colonic lumen in this study, except for Lactococcus. In this pathway, arginine is initially hydrolysed to citrulline and NH3. Thereafter, citrulline is reacted with phosphate and converted to ornithine and carbamoyl-phosphate. Subsequently, carbamoyl-phosphate is catalysed to NH3 and CO2 to generate ATP, whereas ornithine is released (Fig. 3a). Thus, the complete functional pathway requires not only arginine deiminase, but also ornithine carbamoyltransferase and carbamate kinase.39 As this pathway is typically activated by depletion of an energy source,40 it seems only natural that the pathway is active in the colonic lumen, an energy-deficient environment. Furthermore, several studies have reported that NH3 production via this pathway confers resistance to acid stress.41,42 Indeed, a study in Lactobacillus sakei indicated that the pathway is sensitive to pH, i.e. that arginine depletion triggers conversion of citrulline to ornithine, between pH 5.0 and 6.0,42 and a study in Lactobacillus fermentum indicated that the main product of the pathway is ornithine in low-pH conditions.43 Accordingly, we observed a higher ratio of ornithine to citrulline at 4 h and 6 h, at which point faecal cultures had a lower pH. Taken together, these observations suggest that intestinal bacteria take up arginine and release ornithine via this pathway to acquire ATP, which confers resistance to acid stress and thereby maintains viability.
Characterization of the phosphotransacetylase-acetate kinase pathway for ATP production in Porphyromonas gingivalis
Published in Journal of Oral Microbiology, 2019
Yasuo Yoshida, Mitsunari Sato, Takamasa Nonaka, Yoshiaki Hasegawa, Yuichiro Kezuka
All living cells rapidly turn over ATP to satisfy their energy demands, and consequently ATP must be produced from ADP in a process requiring energy. In general, ATP is biosynthesized via substrate-level phosphorylation by enzymes in the cytoplasm, or through electron transfer by ATPases located on mitochondrial (eukaryotes) or cytoplasmic (prokaryotes) membranes. Since ATP production and substrate-level phosphorylation processes are directly coupled, the reactions necessarily liberate the amount of energy required to phosphorylate ADP [65]. Coupling to the phosphorylation of ADP is limited to a small number of molecules for which it is thermodynamically feasible: 1,3-bisphosphoglycerate, succinyl-CoA, phosphoenolpyruvate, arginine phosphate, carbamoyl phosphate, creatine phosphate, butyryl phosphate, and AcP, catalyzed by phosphoglycerate kinase, succinyl-CoA synthetase, pyruvate kinase, arginine kinase, carbamate kinase, creatine kinase, butyrate kinase, and Ack, respectively [65]. Homology searches using complete genome sequences revealed that, apart from phosphoglycerate kinase and PgAck, homologs of these enzymes are not present in P. gingivalis ATCC 33277 or W83 [24,25]. A homolog of phosphoglycerate kinase, one of the major enzymes in glycolysis, is present in the genome of P. gingivalis ATCC 33277 (PGN_0433). Previous experiments using radio-labeled glucose revealed only 5% uptake of glucose from the test medium by P. gingivalis, most of which contributes to cell carbohydrates and their derivatives, suggesting that glucose utilization by this organism is very poor, and carbohydrates do not appear to readily support growth [7]. Therefore, the PGN_0433 protein might not necessarily function as a phosphoglycerate kinase. In addition, apart from PgAck, no other analogs were identified in the genome of P. gingivalis ATCC 33277 or W83. Further studies are therefore needed to clarify the exact mechanism of ATP production in P. gingivalis, but the essentiality of both PgPta and PgAck implies that the Pta-Ack pathway plays an important role in ATP production in this microorganism.