D-glycerate dehydrogenase deficiency

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D-glycerate dehydrogenase deficiency
Other names3-phosphoglycerate dehydrogenase deficiency, PHGDH deficiency, PHGDHD
Autosomal recessive - en.svg
Condition is acquired via an autosomal recessive pattern
Specialty Metabolism
Symptoms Congenital microcephaly, psychomotor retardation and seizures in infants, moderate developmental delay and behavioral disorders juveniles. [1]
Usual onsetAdolescent, Infancy, Childhood
CausesGenetic
PreventionN/A
Treatment Diet
Medication Serine
Prognosis Shortened life expectancy
Frequency<1 / 1 000 000

D-glycerate dehydrogenase deficiency (or 3-phosphoglycerate dehydrogenase deficiency, PHGDH deficiency, PHGDHD) is a rare autosomal metabolic disease where the young patient is unable to produce an enzyme necessary to convert 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the only way for humans to synthesize serine. This disorder is called Neu–Laxova syndrome in neonates.

Contents

Symptoms and signs

Cause

Homozygous or compound heterozygous mutations in 3-phosphoglycerate dehydrogenase (PHGDH) cause Neu-Laxova syndrome [2] [3] and phosphoglycerate dehydrogenase deficiency. [4]

Mechanism

3-Phosphoglycerate dehydrogenase catalyzes the transition of 3-phosphoglycerate into 3-phosphohydroxypyruvate, which is the committed step in the phosphorylated pathway of L-serine biosynthesis. It is also essential in cysteine and glycine synthesis, which lie further downstream. [5] This pathway represents the only way to synthesize serine in most organisms except plants, which uniquely possess multiple synthetic pathways. Nonetheless, the phosphorylated pathway that PHGDH participates in is still suspected to have an essential role in serine synthesis used in the developmental signaling of plants. [6] [7]

Diagnosis

Treatment

Treatment typically involves oral supplementation of serine and glycine. [8] [9]

Related Research Articles

Serine is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain consisting of a hydroxymethyl group, classifying it as a polar amino acid. It can be synthesized in the human body under normal physiological circumstances, making it a nonessential amino acid. It is encoded by the codons UCU, UCC, UCA, UCG, AGU and AGC.

<span class="mw-page-title-main">Threonine</span> Amino acid

Threonine is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group, a carboxyl group, and a side chain containing a hydroxyl group, making it a polar, uncharged amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Threonine is synthesized from aspartate in bacteria such as E. coli. It is encoded by all the codons starting AC.

A congenital disorder of glycosylation is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems in affected infants. The most common sub-type is PMM2-CDG where the genetic defect leads to the loss of phosphomannomutase 2 (PMM2), the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate.

Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-catalyzed processes where chemical substances absorbed as nutrients serve as enzyme substrates, with conversion by the living organism either into simpler or more complex products. Examples of biosynthetic pathways include those for the production of amino acids, lipid membrane components, and nucleotides, but also for the production of all classes of biological macromolecules, and of acetyl-coenzyme A, adenosine triphosphate, nicotinamide adenine dinucleotide and other key intermediate and transactional molecules needed for metabolism. Thus, in biosynthesis, any of an array of compounds, from simple to complex, are converted into other compounds, and so it includes both the catabolism and anabolism of complex molecules. Biosynthetic processes are often represented via charts of metabolic pathways. A particular biosynthetic pathway may be located within a single cellular organelle, while others involve enzymes that are located across an array of cellular organelles and structures.

Methylotrophs are a diverse group of microorganisms that can use reduced one-carbon compounds, such as methanol or methane, as the carbon source for their growth; and multi-carbon compounds that contain no carbon-carbon bonds, such as dimethyl ether and dimethylamine. This group of microorganisms also includes those capable of assimilating reduced one-carbon compounds by way of carbon dioxide using the ribulose bisphosphate pathway. These organisms should not be confused with methanogens which on the contrary produce methane as a by-product from various one-carbon compounds such as carbon dioxide. Some methylotrophs can degrade the greenhouse gas methane, and in this case they are called methanotrophs. The abundance, purity, and low price of methanol compared to commonly used sugars make methylotrophs competent organisms for production of amino acids, vitamins, recombinant proteins, single-cell proteins, co-enzymes and cytochromes.

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

Amino acid biosynthesis 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.

17β-Hydroxysteroid dehydrogenases, also 17-ketosteroid reductases (17-KSR), are a group of alcohol oxidoreductases which catalyze the reduction of 17-ketosteroids and the dehydrogenation of 17β-hydroxysteroids in steroidogenesis and steroid metabolism. This includes interconversion of DHEA and androstenediol, androstenedione and testosterone, and estrone and estradiol.

<span class="mw-page-title-main">Arginine:glycine amidinotransferase</span> Enzyme

L-Arginine:glycine amidinotransferase is the enzyme that catalyses the transfer of an amidino group from L-arginine to glycine. The products are L-ornithine and glycocyamine, also known as guanidinoacetate, the immediate precursor of creatine. Creatine and its phosphorylated form play a central role in the energy metabolism of muscle and nerve tissues. Creatine is in highest concentrations in the skeletal muscle, heart, spermatozoa and photoreceptor cells. Creatine helps buffer the rapid changes in ADP/ATP ratio in muscle and nerve cells during active periods. Creatine is also synthesized in other tissues, such as pancreas, kidneys, and liver, where amidinotransferase is located in the cytoplasm, including the intermembrane space of the mitochondria, of the cells that make up those tissues.

<span class="mw-page-title-main">Glycerate dehydrogenase</span>

In enzymology, a glycerate dehydrogenase (EC 1.1.1.29) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Aspartate-semialdehyde dehydrogenase</span> Amino-acid-synthesizing enzyme in fungi, plants and prokaryota

In enzymology, an aspartate-semialdehyde dehydrogenase is an enzyme that is very important in the biosynthesis of amino acids in prokaryotes, fungi, and some higher plants. It forms an early branch point in the metabolic pathway forming lysine, methionine, leucine and isoleucine from aspartate. This pathway also produces diaminopimelate which plays an essential role in bacterial cell wall formation. There is particular interest in ASADH as disabling this enzyme proves fatal to the organism giving rise to the possibility of a new class of antibiotics, fungicides, and herbicides aimed at inhibiting it.

<span class="mw-page-title-main">PMM2</span> Protein-coding gene in the species Homo sapiens

Phosphomannomutase 2 is an enzyme that in humans is encoded by the PMM2 gene.

<span class="mw-page-title-main">GATM (gene)</span> Protein-coding gene in the species Homo sapiens

Glycine amidinotransferase, mitochondrial is an enzyme that in humans is encoded by the GATM gene.

<span class="mw-page-title-main">PSPH</span> Enzyme found in humans

Phosphoserine phosphatase is an enzyme that in humans is encoded by the PSPH gene.

<span class="mw-page-title-main">Phosphoglycerate dehydrogenase</span> Metabolic enzyme PHGDH

Phosphoglycerate dehydrogenase (PHGDH) is an enzyme that catalyzes the chemical reactions

<span class="mw-page-title-main">Alpha-aminoadipic semialdehyde synthase</span> Protein-coding gene in the species Homo sapiens

Alpha-aminoadipic semialdehyde synthase is an enzyme encoded by the AASS gene in humans and is involved in their major lysine degradation pathway. It is similar to the separate enzymes coded for by the LYS1 and LYS9 genes in yeast, and related to, although not similar in structure, the bifunctional enzyme found in plants. In humans, mutations in the AASS gene, and the corresponding alpha-aminoadipic semialdehyde synthase enzyme are associated with familial hyperlysinemia. This rare disease is inherited in an autosomal recessive pattern and patients often have no clinical symptoms.

<span class="mw-page-title-main">D-Glyceric acidemia</span> Medical condition

D-Glyceric Acidemia is an inherited disease, in the category of inborn errors of metabolism. It is caused by a mutation in the gene GLYCTK, which encodes for the enzyme glycerate kinase.

<span class="mw-page-title-main">PSAT1</span> Protein-coding gene in the species Homo sapiens

Phosphoserine aminotransferase (PSA) also known as phosphohydroxythreonine aminotransferase (PSAT) is an enzyme that in humans is encoded by the PSAT1 gene.

Phosphoserine transaminase is an enzyme with systematic name O-phospho-L-serine:2-oxoglutarate aminotransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Neu–Laxova syndrome</span> Medical condition

Neu–Laxova syndrome is a rare autosomal recessive disorder characterized by severe intrauterine growth restriction and multiple congenital malformations. Neu–Laxova syndrome is a very severe disorder, leading to stillbirth or death shortly after birth. It was first described by Dr. Richard Neu in 1971 and Dr. Renata Laxova in 1972 as a lethal disorder in siblings with multiple malformations. Neu–Laxova syndrome is an extremely rare disorder with fewer than 100 cases reported in medical literature.

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

Achalasia microcephaly syndrome is a rare condition whereby achalasia in the oesophagus manifests alongside microcephaly and intellectual disability. This is a rare constellation of symptoms with a predicted familial trend.

References

  1. "Orphanet: Search by disease name" . Retrieved 1 December 2019.
  2. Shaheen R, Rahbeeni Z, Alhashem A, Faqeih E, Zhao Q, Xiong Y, Almoisheer A, Al-Qattan SM, Almadani HA, Al-Onazi N, Al-Baqawi BS, Saleh MA, Alkuraya FS (Jun 2014). "Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH". American Journal of Human Genetics. 94 (6): 898–904. doi:10.1016/j.ajhg.2014.04.015. PMC   4121479 . PMID   24836451.
  3. Acuna-Hidalgo R, Schanze D, Kariminejad A, Nordgren A, Kariminejad MH, Conner P, Grigelioniene G, Nilsson D, Nordenskjöld M, Wedell A, Freyer C, Wredenberg A, Wieczorek D, Gillessen-Kaesbach G, Kayserili H, Elcioglu N, Ghaderi-Sohi S, Goodarzi P, Setayesh H, van de Vorst M, Steehouwer M, Pfundt R, Krabichler B, Curry C, MacKenzie MG, Boycott KM, Gilissen C, Janecke AR, Hoischen A, Zenker M (Sep 2014). "Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway". American Journal of Human Genetics. 95 (3): 285–93. doi:10.1016/j.ajhg.2014.07.012. PMC   4157144 . PMID   25152457.
  4. Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E (Jun 1996). "3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis". Archives of Disease in Childhood. 74 (6): 542–5. doi:10.1136/adc.74.6.542. PMC   1511571 . PMID   8758134.
  5. "MetaCyc L-serine biosynthesis". biocyc.org. Retrieved 2016-03-01.
  6. Ros R, Muñoz-Bertomeu J, Krueger S (Sep 2014). "Serine in plants: biosynthesis, metabolism, and functions". Trends in Plant Science. 19 (9): 564–9. Bibcode:2014TPS....19..564R. doi:10.1016/j.tplants.2014.06.003. PMID   24999240. S2CID   19690197.
  7. Ho CL, Noji M, Saito M, Saito K (Jan 1999). "Regulation of serine biosynthesis in Arabidopsis. Crucial role of plastidic 3-phosphoglycerate dehydrogenase in non-photosynthetic tissues". The Journal of Biological Chemistry. 274 (1): 397–402. doi: 10.1074/jbc.274.1.397 . PMID   9867856.
  8. de Koning TJ, Duran M, Dorland L, Gooskens R, Van Schaftingen E, Jaeken J, Blau N, Berger R, Poll-The BT (Aug 1998). "Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency". Annals of Neurology. 44 (2): 261–5. doi: 10.1002/ana.410440219 . PMID   9708551. S2CID   46565109.
  9. de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I, Berger R (2004-12-18). "Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency". Lancet. 364 (9452): 2221–2. doi:10.1016/S0140-6736(04)17596-X. PMID   15610810. S2CID   40121728.