Dicarboxylic aminoaciduria

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Dicarboxylic aminoaciduria
Other namesGlutamate-aspartate transport defect [1]
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Dicarboxylic aminoaciduria is a rare form of aminoaciduria (1:35 000 births [2] ) which is an autosomal recessive disorder of urinary glutamate and aspartate due to genetic errors related to transport of these amino acids. [3] Mutations resulting in a lack of expression of the SLC1A1 gene, a member of the solute carrier family, are found to cause development of dicarboxylic aminoaciduria in humans. SLC1A1 encodes for EAAT3 which is found in the neurons, intestine, kidney, lung, and heart. [3] [4] EAAT3 is part of a family of high affinity glutamate transporters which transport both glutamate and aspartate across the plasma membrane.

Contents

Symptoms and signs

Dicarboxylic aminoaciduria involves excretion of urinary glutamate and aspartate, resulting from the incomplete reabsorption of anionic amino acids from the glomerular filtrate in the kidney. [3] This affects a diseased individual's amino acid pool, as they will have to spend additional resources to replenish the amino acids which would have otherwise been present. Additionally, glutamate transporters are responsible for the synaptic release of the glutamate (neurotransmitter) within the interneuronal synaptic cleft. This hindrance of functionality in individuals with dicarboxylic aminoaciduria may be related to growth retardation, intellectual disability, and a tendency toward fasting hypoglycemia and ketoacidosis. [3] [5] Dicarboxylic aminoaciduria is diagnosed by finding the increased presence of glutamate and aspartate in the urine. [3]

Cause

Basic transport of glutamate in the synapse as well as the neuroglia. Glutamatergic Synapse.png
Basic transport of glutamate in the synapse as well as the neuroglia.

Glutamate transporters are proficient at pumping glutamate into cells due to their ability to couple with inorganic ions. [4] Transport of glutamate into the cell requires the coupling of three sodium ions as well as a proton, whereas transport out of the cell requires a single potassium ion. [4] This transport results in two positive charges being displaced across the membrane per cycle. [4] Moreover, this process is dependent on a pH gradient, due to glutamate needing to be protonated prior to transport. [4]

Mutations

Dicarboxylic aminoaciduria is the result of a point mutation of tryptophan to arginine at position 445 and a deletion mutation of isoleucine at position 395. [3] EAAT3 is found in location 9p24, it is primarily expressed in the brain and kidneys. [6]

Metabolism

In the gastrointestinal tract, protein digestion and absorption are key to establishing and maintaining amino acid pools. In the case of dicarboxylic aminoaciduria, where glutamate and aspartate transport are impaired, the alanine, aspartate and glutamate metabolism are affected. Enterocytes in the intestines break up peptides into residual amino acids where they would normally use charge-specific amino acid transporters to get across the epithelial cells. In dicarboxylic aminoaciduria, the anionic amino acid transporter, EAAT3, cannot bring glutamate and aspartate across epithelial cells, leading to them being excreted via the urine.[ citation needed ]

Examples

Below is an example of how glutamate is used to synthesize alanine via alanine transaminase.

Glutamate + pyruvateα-ketoglutarate + Alanine
Alanine transaminase Alanine amino transferase.png
Alanine transaminase

Another example is the conversion of aspartate to glutamate via the enzyme aspartate transaminase.

Aspartate + α-ketoglutarateOxaloacetate + Glutamate
Aspartate transaminase Aspartate aminotransferase reaction.png
Aspartate transaminase

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Diagnosis

Treatment

Related Research Articles

α-Ketoglutaric acid Chemical compound

α-Ketoglutaric acid is a keto acid.

<span class="mw-page-title-main">Alanine</span> Α-amino acid that is used in the biosynthesis of proteins

Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side chain. Consequently, its IUPAC systematic name is 2-aminopropanoic acid, and it is classified as a nonpolar, aliphatic α-amino acid. Under biological conditions, it exists in its zwitterionic form with its amine group protonated (as −NH3+) and its carboxyl group deprotonated (as −CO2). It is non-essential to humans as it can be synthesised metabolically and does not need to be present in the diet. It is encoded by all codons starting with GC (GCU, GCC, GCA, and GCG).

<span class="mw-page-title-main">Glutamic acid</span> Amino acid and neurotransmitter

Glutamic acid is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synthesize enough for its use. It is also the most abundant excitatory neurotransmitter in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABAergic neurons.

<span class="mw-page-title-main">Proximal tubule</span> Segment of nephron in kidneys

The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s capsule abruptly transition to proximal tubule epithelial cells (PTECs). The proximal tubule can be further classified into the proximal convoluted tubule (PCT) and the proximal straight tubule (PST).

<span class="mw-page-title-main">Aspartate transaminase</span> Enzyme involved in amino acid metabolism

Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase, is a pyridoxal phosphate (PLP)-dependent transaminase enzyme that was first described by Arthur Karmen and colleagues in 1954. AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in amino acid metabolism. AST is found in the liver, heart, skeletal muscle, kidneys, brain, red blood cells and gall bladder. Serum AST level, serum ALT level, and their ratio are commonly measured clinically as biomarkers for liver health. The tests are part of blood panels.

<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

<span class="mw-page-title-main">Transaminase</span> Class of enzymes

Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins.

<span class="mw-page-title-main">Cahill cycle</span> Metabolic pathway for transport of energy into and removal of ammonia from muscles

The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients between skeletal muscle and the liver. When muscles degrade amino acids for energy needs, the resulting nitrogen is transaminated to pyruvate to form alanine. This is performed by the enzyme alanine transaminase (ALT), which converts L-glutamate and pyruvate into α-ketoglutarate and L-alanine. The resulting L-alanine is shuttled to the liver where the nitrogen enters the urea cycle and the pyruvate is used to make glucose.

Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. In the brain, EAATs remove glutamate from the synaptic cleft and extrasynaptic sites via glutamate reuptake into glial cells and neurons, while VGLUTs move glutamate from the cell cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues, including the heart, liver, testes, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.

<span class="mw-page-title-main">Excitatory amino acid transporter 4</span> Protein found in humans

Excitatory amino-acid transporter 4 (EAAT4) is a protein that in humans is encoded by the SLC1A6 gene.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids. These 11 are called the non-essential amino acids).

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Excitatory amino acid transporter 1</span> Protein found in humans

Excitatory amino acid transporter 1 (EAAT1) is a protein that, in humans, is encoded by the SLC1A3 gene. EAAT1 is also often called the GLutamate ASpartate Transporter 1 (GLAST-1).

The mitochondrial shuttles are biochemical transport systems used to transport reducing agents across the inner mitochondrial membrane. NADH as well as NAD+ cannot cross the membrane, but it can reduce another molecule like FAD and [QH2] that can cross the membrane, so that its electrons can reach the electron transport chain.

<span class="mw-page-title-main">Excitatory amino acid transporter 3</span> Protein found in humans

Excitatory amino acid transporter 3 (EAAT3), is a protein that in humans is encoded by the SLC1A1 gene.

Glutaminolysis (glutamine + -lysis) is a series of biochemical reactions by which the amino acid glutamine is lysed to glutamate, aspartate, CO2, pyruvate, lactate, alanine and citrate.

<span class="mw-page-title-main">Sodium-dependent neutral amino acid transporter B(0)AT1</span> Protein-coding gene in the species Homo sapiens

Sodium-dependent neutral amino acid transporter B(0)AT1 is a protein that in humans is encoded by the SLC6A19 gene.

In biochemistry, the glutamate–glutamine cycle is a cyclic metabolic pathway which maintains an adequate supply of the neurotransmitter glutamate in the central nervous system. Neurons are unable to synthesize either the excitatory neurotransmitter glutamate, or the inhibitory GABA from glucose. Discoveries of glutamate and glutamine pools within intercellular compartments led to suggestions of the glutamate–glutamine cycle working between neurons and astrocytes. The glutamate/GABA–glutamine cycle is a metabolic pathway that describes the release of either glutamate or GABA from neurons which is then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of either glutamate or GABA.

<span class="mw-page-title-main">Iminoglycinuria</span> Medical condition

Iminoglycinuria is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline. This results in excess urinary excretion of all three acids.

An excitatory amino acid reuptake inhibitor (EAARI) is a type of drug which inhibits the reuptake of the excitatory neurotransmitters glutamate and aspartate by blocking one or more of the excitatory amino acid transporters (EAATs).

References

  1. "Dicarboxylic aminoaciduria | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 16 April 2019.
  2. Camargo SM, Bockenhauer D, Kleta R (April 2008). "Aminoacidurias: Clinical and molecular aspects". Kidney Int. 73 (8): 918–25. doi: 10.1038/sj.ki.5002790 . PMID   18200002.
  3. 1 2 3 4 5 6 Bailey CG, Ryan RM, Thoeng AD, Ng C, King K, Vanslambrouck JM, Auray-Blais C, Vandenberg RJ, Bröer S, Rasko JE (January 2011). "Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria". J. Clin. Invest. 121 (1): 446–53. doi:10.1172/JCI44474. PMC   3007158 . PMID   21123949.
  4. 1 2 3 4 5 Hediger MA (October 1999). "Glutamate transporters in kidney and brain". Am. J. Physiol. 277 (4 Pt 2): F487–92. doi: 10.1152/ajprenal.1999.277.4.F487 . PMID   10516270.
  5. Bröer S. (January 2008). "Amino acid transport across mammalian intestinal and renal epithelia". Physiol. Rev. 88 (1): 249–86. doi:10.1152/physrev.00018.2006. PMID   18195088.
  6. Smith CP, Weremowicz S, Kanai Y, Stelzner M, Morton CC, Hediger MA (March 1994). "Assignment of the gene coding for the human high-affinity glutamate transporter EAAC1 to 9p24: potential role in dicarboxylic aminoaciduria and neurodegenerative disorders". Genomics. 20 (2): 335–336. doi:10.1006/geno.1994.1183. PMID   8020993.