Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS)

Kondori, Nazanin Rahmani; Paul, Praveen; Robbins, Jacqueline; Liu, Ke; Hildyard, John C. W.; Wells, Dominic J.; Belleroche, Jacqueline de

doi:10.3389/fmolb.2018.00008

Cited by 23 publications

(17 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DAO has been shown to play a detoxifying role in the kidneys, as it helps maintain low d ‐amino acid levels . Since it controls d ‐serine levels, DAO activity in the CNS has been associated with conditions affecting N ‐methyl‐ d ‐aspartate (NMDA) receptor signaling/dysfunction, including schizophrenia, amyotrophic lateral sclerosis and Alzheimer's disease . DAO in leukocytes was shown to play a bactericidal role against certain bacteria in vitro , while in vivo this effect remains controversial .…”

Section: Introductionsupporting

confidence: 87%

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

2020

View full text Add to dashboard Cite

D-amino acid oxidase (DAO) is a peroxisomal enzyme that catalyzes the oxidative deamination of several neutral and basic D-amino acids to their corresponding -keto acids. In most mammalian species studied, high DAO activity is found in the kidney, liver, brain and polymorphonuclear leukocytes, and its main function is to maintain low circulating D-amino acid levels. DAO expression and activity have been associated with acute and chronic kidney diseases and with several pathologies related to N-methyl-D-aspartate (NMDA) receptor hypo/hyper-function;however, its precise role is not completely understood. In the present study we show that DAO activity can be detected in vivo in the rat kidney using hyperpolarized D-[1-13 C]alanine.Following a bolus of hyperpolarized D-alanine, accumulation of pyruvate, lactate and bicarbonate was observed only when DAO activity was not inhibited. The measured lactate-to-D-alanine ratio was comparable to the values measured when the L-enantiomer was injected. Metabolites downstream of DAO were not observed when scanning the liver and brain. The conversion of hyperpolarized D-[1-13 C]alanine to lactate and pyruvate was detected in blood ex vivo, and lactate and bicarbonate were detected on scanning the blood pool in the heart in vivo; however, the bicarbonate-to-D-alanine ratio was significantly lower compared with the kidney. These results demonstrate that the specific metabolism of the two enantiomers of hyperpolarized [1-13 C]alanine in the kidney and in the blood can be distinguished, underscoring the potential of D-[1-13 C]alanine as a probe of D-amino acid metabolism. INTRODUCTIONWhile being less abundant than L-amino acids, D-amino acids are widespread in nature and take part in normal mammalian metabolism. Aside from D-serine and D-aspartate, which humans can synthesize endogenously, most D-amino acids are taken up through the diet, and their levels are regulated by D-amino acid oxidase (DAO) and D-aspartate oxidase. 1 DAO, a peroxisomal flavoenzyme, catalyzes the conversion of basic and neutral D-amino acids into the corresponding -keto acids in two steps. First, the D-amino acid is oxidized to an imino acid, and the flavin adenine dinucleotide coenzyme is concomitantly reduced. The imino acid then undergoes non-enzymatic hydrolysis to yield the -keto acid and ammonia. In mammals, DAO is abundantly present in the kidneys, where it is expressed in the epithelial cells of the S2 and S3 segments of the proximal tubules. Although it is also expressed in hepatocytes, in the central nervous system (CNS) and in polymorphonuclear (PMN) leukocytes, the physiological and pathological role of D-amino acids and DAO in these tissues is not completely understood. DAO has been shown to play a detoxifying role in the kidneys, as it helps maintain low D-amino acid levels. 2 Since it controls D-serine levels, DAO activity in the CNS has been associated with conditions affecting N-methyl-D-aspartate (NMDA) receptor signaling/dysfunction, including schizophrenia, 3 amyotrophic lateral sclerosis ...

show abstract

Section: Introductionsupporting

confidence: 87%

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

2020

View full text Add to dashboard Cite

show abstract

“…d-Ser is an important and abundant substance that works as a neurotransmitter in the mammalian brain [10,11]. d-Ser functions as the coagonist of the N-methyl-d-aspartate receptor, which relates to the higher functions of the mammalian brain, and d-Ser has been reported to be involved in various diseases, such as schizophrenia [12,13] and amyotrophic lateral sclerosis [14]. Furthermore, it has been recently revealed that d-Ser is involved in synapse and dendrite formation in the brain [15,16].…”

Section: D-amino Acids In Mammalsmentioning

confidence: 99%

d-Amino Acids and Lactic Acid Bacteria

Kobayashi

2019

Microorganisms

View full text Add to dashboard Cite

Proteins are composed of l-amino acids except for glycine, which bears no asymmetric carbon atom. Accordingly, researchers have studied the function and metabolism of l-amino acids in living organisms but have paid less attention to the presence and roles of their d-enantiomers. However, with the recent developments in analytical techniques, the presence of various d-amino acids in the cells of various organisms and the importance of their roles have been revealed. For example, d-serine (d-Ser) and d-aspartate (d-Asp) act as neurotransmitters and hormone-like substances, respectively, in humans, whereas some kinds of d-amino acids act as a biofilm disassembly factor in bacteria. Interestingly, lactic acid bacteria produce various kinds of d-amino acids during fermentation, and many d-amino acids taste sweet, compared with the corresponding l-enantiomers. The influence of d-amino acids on human health and beauty has been reported in recent years. These facts suggest that the d-amino acids produced by lactic acid bacteria are important in terms of the taste and function of lactic-acid-fermented foods. Against this background, unique d-amino-acid-metabolizing enzymes have been searched for and observed in lactic acid bacteria. This review summarizes and introduces the importance of various d-amino acids in this regard.Proteins are basically made up of 20 kinds of α-amino acids in the form of monomers, and these amino acids have at least one asymmetric carbon, except for glycine. This yields 19 kinds of amino acid (glycine has been excepted) with l-and d-form varieties. As proteins are made up of l-amino acids, many researchers, in fields such as medical, food, and nutritional science, have paid close attention to l-amino acids, giving rise to considerable knowledge of l-amino acids, including proteins. Until the 1970s, many researchers thought that d-amino acids were rare in nature and did not play an important role in living organisms. After that, however, d-alanine (d-Ala), d-glutamate (d-Glu), and d-aspartate (d-Asp) were found in bacterial cell walls as constituents, and d-amino acids were observed to exist in nature. This finding led to the conclusion that d-amino acids were only rarely present in bacterial cell walls, but in the 1990s, the development of analytical techniques, such as chiral column chromatography, meant that various kinds of d-amino acids were identified in free forms in diverse organisms. These d-amino acids were initially considered to be derived from foods or enterobacteria, but it is now known that some parts of d-amino acids such as d-serine (d-Ser) and d-Asp can be synthesized in mammalian cells. d-Amino acids have similar physical and chemical characteristics with l-amino acids, but the physiological functions of d-amino acids are completely different with those of l-amino acids. For example, d-Ser works as neurotransmitter in the brain, but l-Ser has no such role. Furthermore, d-amino acids are uncommon in living organisms, compared with l-amino acids, and despite the fact that some d-...

show abstract

“…It is of high interest since it has been linked to various medical conditions, for example decreased Dserine levels have been associated with the hyperfunction of NMDA receptors in schizophrenia as well as the cognitive impairments observed during aging [33]. Elevated D-serine levels in the spinal cord of patients with amyotrophic lateral sclerosis are also believed to mediate motor neuron degeneration [33,34]. Metabolic modelling approaches such as used in this study could, therefore, perhaps be a valuable tool to help gain deeper understanding of its metabolism in these cases.…”

Section: D-serine Secretionmentioning

confidence: 99%

Amino Acid Requirements of the Chinese Hamster Ovary Cell Metabolism during Recombinant Protein Production

Traustason

2019

Preprint

View full text Add to dashboard Cite

Majority of biopharmaceutical drugs today are produced by Chinese hamster ovary (CHO) cells, which have been the standard industry host for the past decades. To produce and secrete a substantial amount of the target recombinant proteins the CHO cells must be provided with suitable growth conditions and provided with the necessary nutrients. Amino acids play a key role in this as the building blocks of proteins, playing important roles in a large number of metabolic pathways and being important sources of nitrogen as well as carbon under certain conditions. In this study exploratory analysis of the amino acid requirements of CHO cells was carried out using metabolic modelling approaches. Flux balance analysis was employed to evaluate the optimal distribution of fluxes in a genome-scale model of CHO cells to gain information on the cells' metabolic response in silico.The results showed that providing non-essential amino acids (NEAAs) has a positive effect on CHO cell biomass production and that cysteine as well as tyrosine play a fundamental role in this.This implies that extracellular provision of NEAAs limits the extent of energy loss in amino acid biosynthetic pathways and renders additional reducing power available for other biological processes.Detailed analysis of the possible secretion and uptake of D-serine in the CHO model was also performed and its influence on the rest of the metabolism mapped out, which revealed results matching various existing literature. This is interesting since no mention of D-serine in regard to CHO cells was found in current literature, as well as the fact that this opens up the possibility of using the model for better understanding of certain disorders in higher up organisms that have been implicated with D-serine, such as motor neuron and cognitive degeneration. Finally, outcome from the model optimisation of different recombinant proteins demonstrated clearly how the difference in protein structure and size can influence the production outcome. These results show that systematic and model-based approaches have great potential for broad de novo exploration as well as being able to handle the cellular burden associated with the production of different types of recombinant protein.

show abstract

Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS)

Cited by 23 publications

References 37 publications

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

d-Amino Acids and Lactic Acid Bacteria

Amino Acid Requirements of the Chinese Hamster Ovary Cell Metabolism during Recombinant Protein Production

Contact Info

Product

Resources

About

Focus on the Role of D-serine and D-amino Acid Oxidase in Amyotrophic Lateral Sclerosis/Motor Neuron Disease (ALS)

Cited by 23 publications

References 37 publications

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐13C]alanine

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐13C]alanine

d-Amino Acids and Lactic Acid Bacteria

Amino Acid Requirements of the Chinese Hamster Ovary Cell Metabolism during Recombinant Protein Production

Contact Info

Product

Resources

About

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine

In vivo detection of d‐amino acid oxidase with hyperpolarized d‐[1‐¹³C]alanine