How we Think

Recent years have witnessed the discovery that amino acids (AA) are not only cell signaling molecules but are also regulators of gene expression and the protein phosphorylation cascade. Additionally, AA are key precursors for syntheses of hormones and low-molecular weight nitrogenous substances with each having enormous biological importance. Physiological concentrations of AA and their metabolites (e.g., nitric oxide, polyamines, glutathione, taurine, thyroid hormones, and serotonin) are required for the functions. However, elevated levels of AA and their products (e.g., ammonia, homocysteine, and asymmetric dimethylarginine) are pathogenic factors for neurological disorders, oxidative stress, and cardiovascular disease. Thus, an optimal balance among AA in the diet and circulation is crucial for whole body homeostasis. There is growing recognition that besides their role as building blocks of proteins and polypeptides, some AA regulate key metabolic pathways that are necessary for maintenance, growth, reproduction, and immunity. They are called functional AA, which include arginine, cysteine, glutamine, leucine, proline, and tryptophan. Dietary supplementation with one or a mixture of these AA may be beneficial for (1) ameliorating health problems at various stages of the life cycle (e.g., fetal growth restriction, neonatal morbidity and mortality, weaning-associated intestinal dysfunction and wasting syndrome, obesity, diabetes, cardiovascular disease, the metabolic syndrome, and infertility); (2) optimizing efficiency of metabolic transformations to enhance muscle growth, milk production, egg and meat quality and athletic performance, while preventing excess fat deposition and reducing adiposity. Thus, AA have important functions in both nutrition and health.

Amino acids: metabolism, functions, and nutrition

The transport of amino acids in kidney and intestine is critical for the supply of amino acids to all tissues and the homeostasis of plasma amino acid levels. This is illustrated by a number of inherited disorders affecting amino acid transport in epithelial cells, such as cystinuria, lysinuric protein intolerance, Hartnup disorder, iminoglycinuria, dicarboxylic aminoaciduria, and some other less well-described disturbances of amino acid transport. The identification of most epithelial amino acid transporters over the past 15 years allows the definition of these disorders at the molecular level and provides a clear picture of the functional cooperation between transporters in the apical and basolateral membranes of mammalian epithelial cells. Transport of amino acids across the apical membrane not only makes use of sodium-dependent symporters, but also uses the proton-motive force and the gradient of other amino acids to efficiently absorb amino acids from the lumen. In the basolateral membrane, antiporters cooperate with facilitators to release amino acids without depleting cells of valuable nutrients. With very few exceptions, individual amino acids are transported by more than one transporter, providing backup capacity for absorption in the case of mutational inactivation of a transport system.

Amino acid transport across mammalian intestinal and renal epithelia.

Palacin, Manuel, Raul Estevez, Joan Bertran, and Antonio Zorzano. Molecular Biology of Mammalian Plasma Membrane Amino Acid Transporters. Physiol. Rev. 78: 969–1054, 1998. — Molecular biology ente...

Molecular Biology of Mammalian Plasma Membrane Amino Acid Transporters

SUSCEPTIBILITY of rodent cells to infection by ecotropic murine leukaemia viruses (MuLV) is determined by binding of the virus envelope to a membrane receptor that has multiple membrane-spanning domains1. Cells infected by ecotropic MuLV synthesize envelope protein, gp70, which binds to this receptor, thereby preventing additional infections. The consequences of envelope-MuLV receptor binding for the infected host cell have not been directly determined, partly because the cellular function of the MuLV receptor protein is unknown. Here we report a coincidence in the positions of the first eight putative membrane-spanning domains found in the virus receptor1 and in two related proteins2, the arginine2–4 and histidine2,3,5 permeases of Saccharomyces cerevisiae (Fig. 1), but not in any other proteins identified by computer-based sequence comparison of the Gen Bank data base1. Xenopus oocytes injected with receptor-encoding messenger RNA show increased uptake of L-arginine, L-lysine and L-ornithine. The transport properties and the expression pattern of the virus receptor behave in ways previously attributed to y+ (refs 6, 7), the principal transporter of cationic L-amino acids in mammalian cells.

Transport of cationic amino acids by the mouse ecotropic retrovirus receptor

Two-cell mouse conceptuses were cultured in media that contained various concentrations of inorganic ions and amino acids. Substrates of the amino acid transport system Gly were detrimental to development at slightly hyposmotic concentrations of other ions. In contrast, these amino acids increased the frequency at which two-cell conceptuses developed into blastocysts at total ion concentrations of 355 to 405 mM. Data reported elsewhere is consistent with the possibility that the total ion concentration in oviductal fluid exceeds 360 mM, whereas the concentration of glycine in this fluid may be on the order of 10 mM. Therefore, a high ion concentration and glycine may counteract the potentially harmful effects of each other in situ. Like some marine organisms, preimplantation mouse conceptuses may use glycine as an intracellular osmolite because accumulation of inorganic ions could perturb the activities of some enzymes.

Glycine protects preimplantation mouse conceptuses from a detrimental effect on development of the inorganic ions in oviductal fluid.

Amino acids are essential components of media utilized to culture fertilized human eggs to the blastocyst stage in vitro. Use of such media has led to a significant increase in the proportion of embryos that implant upon transfer to the uterus and to a decrease in the number that need to be transferred to achieve pregnancy. Little is known about the mechanisms by which amino acids foster development of healthy human blastocysts. Indications are, however, that many of these mechanisms are the same in human and mouse embryos. Both essential and nonessential amino acid transport benefit preimplantation mouse embryo development, albeit at different stages. Nonessential amino acid transport improves development primarily during cleavage, whereas essential amino acid transport supports development of more viable embryos, especially subsequent to the eight-cell stage. This review discusses likely mechanisms for these beneficial effects.

https://bioone.org/journals/Biology-of-Reproduction/volume-64/issue-1/biolreprod64.1.1/Amino-Acid-Transport-Regulation-and-Early-Embryo-Development/10.1095/biolreprod64.1.1.pdf

Amino Acid Transport Regulation and Early Embryo Development

Mouse blastocyst outgrowth in vitro and probably implantation in vivo require amino acid signaling via the target of rapamycin (TOR) pathway. This signaling does not simply support protein synthesis and trophoblast differentiation. Rather, it regulates development of trophoblast protrusive activity and may act as a developmental checkpoint for implantation. Moreover, intracellular amino acids per se are insufficient to elicit TOR signaling. Instead, de novo transport of amino acids, and particularly of leucine, stimulate mTOR activity at the blastocyst stage. The activity of the broad-scope and yet leucine-selective amino acid transport system B0,+ could produce such increases in intracellular amino acid concentrations. For example, system B0,+ uses a Na+ gradient to drive amino acid uptake, and the Na+ concentration in uterine secretions increases by nearly two-fold about 18 h before implantation. The resultant mTOR signaling could trigger polyamine, insulin-like growth factor II, and nitric oxi...

https://bioone.org/journals/biology-of-reproduction/volume-69/issue-4/biolreprod.103.018010/Amino-Acid-Transport-Regulates-Blastocyst-Implantation1/10.1095/biolreprod.103.018010.pdf

Amino Acid Transport Regulates Blastocyst Implantation

Objective. To validate the Jefferson Scale of Empathy-Health Profession Students version (JSE-HPS) in pharmacy students.Methods. The JSE-HPS (20 items), adapted from the original Jefferson Scale of...

/pdf/measuring-empathy-in-pharmacy-students-1y91g33suq.pdf

Lon J. Van Winkle

Papers

Glycine protects preimplantation mouse conceptuses from a detrimental effect on development of the inorganic ions in oviductal fluid.

Amino Acid Transport Regulation and Early Embryo Development

Amino Acid Transport Regulates Blastocyst Implantation

Measuring Empathy in Pharmacy Students

Amino acid transport in developing animal oocytes and early conceptuses