Transport of Amino Acids in the Fetus and Neonate

Introduction

Amino acids are the building blocks for proteins and are critical for growth. In addition, they are involved in many metabolic processes within mammalian cells. Thus, regulating their circulating concentrations in the bloodstream is very important for many metabolic processes, including protein synthesis, which results in the growth and development of the fetus and neonate. This chapter reviews the regulation of amino acid transport in the fetus and the newborn. This will include a general description of epithelial transport systems for amino acids, including a more detailed description of the various classes of amino acid transporters that are known. The developmental expression of these transporters in the placenta and the developing kidney will also be discussed. In addition, the role these transporters play in the placenta of neonates with intrauterine growth restriction will be discussed.

Epithelial Transport of Amino Acids

Amino acids are hydrophilic molecules and therefore do not easily diffuse through lipid bilayer membranes. There are a number of transport systems that facilitate the diffusion of amino acids through cell membranes. In addition, the epithelia of the proximal tubule of the kidney, the small intestine, and the syncytiotrophoblast of the placenta have active transport systems to move amino acids from one compartment to another against a concentration gradient. These active transport systems derive their energy from the inwardly directed sodium gradient that is generated from the sodium-potassium ATPase. This is depicted in a generic epithelial cell in Fig. 100.1 . One side of the epithelial cell is the lumen , and the opposite membrane is the basolateral membrane. The sodium-potassium ATPase is located on the basolateral membrane and is responsible for maintaining a very low intracellular sodium concentration. Thus, the amino acid transporter located on the luminal membrane can harness the sodium gradient energy to transport amino acids from the lumen into the cell. The concentration of the amino acid in the cell then becomes much higher than that in the lumen and the bloodstream, and thus the amino acid can diffuse through the basolateral membrane by way of a facilitative transporter into the bloodstream.

Although this transport system seems very simple for many of the solutes reabsorbed in the proximal tubule, it is much more complicated for amino acid transport because amino acids have several different structural classes. Another feature that makes these systems complicated is that some amino acids can be transported by more than one system but with different affinities. There are five known systems of amino acid transporters responsible for the different classes of amino acids. The nomenclature for these systems has also become very complex owing to the history of the discovery of these systems. A full discussion of all the known amino acid transporters is beyond the scope of this chapter (see Broer for a more in-depth review). These systems will be reviewed briefly, and their development in the kidney and placenta will be discussed.

Neutral Amino Acids

The first system is designed to transport neutral amino acids and is depicted in Fig. 100.2 . ^, As shown in the figure, the transporters found in the proximal convoluted tubule are very similar to those found in the small intestine. The proximal straight tubule, in general, has different amino acid transporters that have higher affinities for the amino acids because their concentrations in the lumen of the tubule will be much lower. The transporters on the basolateral membrane of the tubule have been much less characterized, so in Fig. 100.2 there are question marks on those transporters.

The main protein that has been identified in the system has been labeled B ⁰ AT1, as shown in Fig. 100.2 . ^, This transporter carries one sodium ion with the amino acid molecule, so it uses the sodium gradient as the energy source for active transport. The transporters on the basolateral membrane are less well characterized but serve to facilitate the diffusion of the amino acids out of the cell and into the bloodstream. The primary protein, TAT1, is a facilitative transporter that allows the amino acid to go down its concentration gradient from the intracellular compartment into the interstitial fluid. From the interstitial fluid compartment, the amino acid will diffuse into the bloodstream.

Box 100.1 lists the various amino acids that are transported by this system in order of their affinities. As shown, a number of the amino acids that can be carried by the B ⁰ AT1 transporter are also substrates for other transporters; for example, the cationic amino acid transporter also transports cystine actively.

Mutations in these neutral amino acid transporters result in several diseases. Hartnup disorder is caused by a mutation in B ⁰ AT1 depicted in Fig. 100.2 . ^, People with this disorder can develop a pellagra-like rash, as well as cerebellar ataxia, and exhibit aminoaciduria of neutral amino acids, including tryptophan. Tryptophan is a precursor of niacin. Thus, people with Hartnup disorder can easily become niacin deficient and often require supplementation. Another disorder resulting in tryptophan malabsorption is known as blue diaper syndrome. This blue diaper syndrome is secondary to the increased amounts of tryptophan in the stool and urine, which are converted by bacteria into compounds known as indoles. These compounds can then be metabolized to indigo, which causes the blue coloration in the diapers. Although the transporter that is mutated in this syndrome has not been identified, a candidate protein is TAT1, which is located on the basolateral membrane (see Fig. 100.2 ). Recently, a patient with this syndrome was found to have a mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1) . It remains unclear if this syndrome is the result of a defect in amino acid transport or possibly a defect in protein metabolism.