Aminosaurs, Valine
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Valine

Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain isopropyl group, making it a non-polar aliphatic amino acid. Valine is essential in humans, meaning the body cannot synthesize it; it must be obtained from dietary sources which are foods that contain proteins, such as meats, dairy products, soy products, beans and legumes. It is encoded by all codons starting with GU (GUU, GUC, GUA, and GUG).

History and etymology

Valine was first isolated from casein in 1901 by Hermann Emil Fischer.

  • “Valine”. Encyclopædia Britannica Online. Retrieved 6 December 2015.

The name valine comes from its structural similarity to valeric acid, which in turn is named after the plant valerian due to the presence of the acid in the roots of the plant.

  • “Valine”. Merriam-Webster Online Dictionary. Retrieved 6 December 2015.
  • “Valeric acid”. Merriam-Webster Online Dictionary. Retrieved 6 December 2015.

Nomenclature

According to IUPAC, carbon atoms forming valine are numbered sequentially starting from 1 denoting the carboxyl carbon, whereas 4 and 4′ denote the two terminal methyl carbons.

Metabolism

Source and biosynthesis

Valine, like other branched-chain amino acids, is synthesized by bacteria and plants, but not by animals.

It is therefore an essential amino acid in animals, and needs to be present in the diet. Adult humans require about 24 mg/kg body weight daily.

It is synthesized in plants and bacteria via several steps starting from pyruvic acid. The initial part of the pathway also leads to leucine. The intermediate α-ketoisovalerate undergoes reductive amination with glutamate.

  • Lehninger, Albert L.; Nelson, David L.; Cox, Michael M. (2000). Principles of Biochemistry (3rd ed.). New York: W. H. Freeman. ISBN 1-57259-153-6..

Enzymes involved in this biosynthesis include:

  1. Acetolactate synthase (also known as acetohydroxy acid synthase)
  2. Acetohydroxy acid isomeroreductase
  3. Dihydroxyacid dehydratase
  4. Valine aminotransferase

Degradation

Like other branched-chain amino acids, the catabolism of valine starts with the removal of the amino group by transamination, giving alpha-ketoisovalerate, an alpha-keto acid, which is converted to isobutyryl-CoA through oxidative decarboxylation by the branched-chain α-ketoacid dehydrogenase complex.

  • Mathews CK (2000). Biochemistry. Van Holde, K. E., Ahern, Kevin G. (3rd ed.). San Francisco, Calif.: Benjamin Cummings. p. 776. ISBN 978-0-8053-3066-3. OCLC 42290721.

This is further oxidised and rearranged to succinyl-CoA, which can enter the citric acid cycle.

Synthesis

Racemic valine can be synthesized by bromination of isovaleric acid followed by amination of the α-bromo derivative.

HO2CCH2CH(CH3)2 + Br2 → HO2CCHBrCH(CH3)2 + HBrHO2CCHBrCH(CH3)2 + 2 NH3 → HO2CCH(NH2)CH(CH3)2 + NH4Br

Medical significance

Metabolic diseases

The degradation of valine is impaired in the following metabolic diseases:

Insulin resistance

Lower levels of serum valine, like other branched-chain amino acids, are associated with weight loss and decreased insulin resistance: higher levels of valine are observed in the blood of diabetic mice, rats, and humans.

Mice fed a BCAA-deprived diet for one day had improved insulin sensitivity, and feeding of a valine-deprived diet for one week significantly decreases blood glucose levels.

  • Xiao F, Yu J, Guo Y, Deng J, Li K, Du Y, et al. (June 2014). “Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice”. Metabolism. 63 (6): 841–50. doi:10.1016/j.metabol.2014.03.006. PMID 24684822.

In diet-induced obese and insulin resistant mice, a diet with decreased levels of valine and the other branched-chain amino acids resulted in a rapid reversal of the adiposity and an improvement in glucose-level control.

The valine catabolite 3-hydroxyisobutyrate promotes insulin resistance in mice by stimulating fatty acid uptake into muscle and lipid accumulation.

In mice, a BCAA-restricted diet decreased fasting blood glucose levels and improved body composition.

Hematopoietic stem cells

Dietary valine is essential for hematopoietic stem cell (HSC) self-renewal, as demonstrated by experiments in mice.

Dietary valine restriction selectively depletes long-term repopulating HSC in mouse bone marrow. Successful stem cell transplantation was achieved in mice without irradiation after 3 weeks on a valine restricted diet. Long-term survival of the transplanted mice was achieved when valine was returned to the diet gradually over a 2-week period to avoid refeeding syndrome, a metabolic disturbance which occurs as a result of reinstitution of nutrition in people who are starved, severely malnourished, or metabolically stressed because of severe illness. When too much food or liquid nutrition supplement is eaten during the initial four to seven days following a malnutrition event, the production of glycogen, fat and protein in cells may cause low serum concentrations of potassium, magnesium and phosphate. The electrolyte imbalance may cause neurologic, pulmonary, cardiac, neuromuscular, and hematologic symptoms—many of which, if severe enough, may result in death.

See also

References

  1. “Physicochemical Information”. emdmillipore. 2022. Retrieved 17 November 2022.
  2. Dawson RM, Elliott DC, Elliott WH, Jones KM, eds. (1959). Data for Biochemical Research. Oxford: Clarendon Press. ASIN B000S6TFHA. OCLC 859821178.
  3. Weast RC, ed. (1981). CRC Handbook of Chemistry and Physics (62nd ed.). Boca Raton, FL: CRC Press. p. C-569. ISBN 0-8493-0462-8.
  4. “Nomenclature and Symbolism for Amino Acids and Peptides”. IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.
  5. “Valine”. Encyclopædia Britannica Online. Retrieved 6 December 2015.
  6. “Valine”. Merriam-Webster Online Dictionary. Retrieved 6 December 2015.
  7. “Valeric acid”. Merriam-Webster Online Dictionary. Retrieved 6 December 2015.
  8. Jones JH, ed. (1985). Amino Acids, Peptides and Proteins. Specialist Periodical Reports. Vol. 16. London: Royal Society of Chemistry. p. 389. ISBN 978-0-85186-144-9.
  9. Basuchaudhuri P (2016). Nitrogen metabolism in rice. Boca Raton, Florida: CRC Press. p. 159. ISBN 978-1-4987-4668-7. OCLC 945482059.
  10. Institute of Medicine (2002). “Protein and Amino Acids”. Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press. pp. 589–768. doi:10.17226/10490. ISBN 978-0-309-08537-3.
  11. Lehninger, Albert L.; Nelson, David L.; Cox, Michael M. (2000). Principles of Biochemistry (3rd ed.). New York: W. H. Freeman. ISBN 1-57259-153-6..
  12. Mathews CK (2000). Biochemistry. Van Holde, K. E., Ahern, Kevin G. (3rd ed.). San Francisco, Calif.: Benjamin Cummings. p. 776. ISBN 978-0-8053-3066-3. OCLC 42290721.
  13. Marvel CS (1940). “dl-Valine”. Organic Syntheses. 20: 106; Collected Volumes, vol. 3, p. 848..
  14. Lynch CJ, Adams SH (December 2014). “Branched-chain amino acids in metabolic signalling and insulin resistance”. Nature Reviews. Endocrinology. 10 (12): 723–36. doi:10.1038/nrendo.2014.171. PMC 4424797. PMID 25287287.
  15. Xiao F, Yu J, Guo Y, Deng J, Li K, Du Y, et al. (June 2014). “Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice”. Metabolism. 63 (6): 841–50. doi:10.1016/j.metabol.2014.03.006. PMID 24684822.
  16. Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, et al. (February 2018). “Restoration of metabolic health by decreased consumption of branched-chain amino acids”. The Journal of Physiology. 596 (4): 623–645. doi:10.1113/JP275075. PMC 5813603. PMID 29266268.
  17. Jang C, Oh SF, Wada S, Rowe GC, Liu L, Chan MC, et al. (April 2016). “A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance”. Nature Medicine. 22 (4): 421–6. doi:10.1038/nm.4057. PMC 4949205. PMID 26950361.
  18. Fontana L, Cummings NE, Arriola Apelo SI, Neuman JC, Kasza I, Schmidt BA, et al. (July 2016). “Decreased Consumption of Branched-Chain Amino Acids Improves Metabolic Health”. Cell Reports. 16 (2): 520–530. doi:10.1016/j.celrep.2016.05.092. PMC 4947548. PMID 27346343.
  19. Taya Y, Ota Y, Wilkinson AC, Kanazawa A, Watarai H, Kasai M, et al. (December 2016). “Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation”. Science. 354 (6316): 1152–1155. Bibcode:2016Sci…354.1152T. doi:10.1126/science.aag3145. PMID 27934766. S2CID 45815137.
  20. Mehanna HM, Moledina J, Travis J (June 2008). “Refeeding syndrome: what it is, and how to prevent and treat it”. BMJ. 336 (7659): 1495–8. doi:10.1136/bmj.a301. PMC 2440847. PMID 18583681.
  21. Doig, GS; Simpson, F; Heighes; Bellomo, R; Chesher, D; Caterson, ID; Reade, MC; Harrigan, PWJ (2015-12-01). “Restricted versus continued standard caloric intake during the management of refeeding syndrome in critically ill adults: a randomised, parallel-group, multicentre, single-blind controlled trial”. The Lancet Respiratory Medicine. 3 (12): 943–952. doi:10.1016/S2213-2600(15)00418-X. ISSN 2213-2619. PMID 26597128.
  • Valine MS Spectrum
  • Isoleucine and valine biosynthesis
  • Valine’s relationship to prions
    • This article was published more than 9 years ago (Washington Post)


      How a history of eating human brains protected this tribe from brain disease
    • By Sarah Kaplan June 11, 2015 at 6:57 a.m. EDT


      A real human brain is displayed in the 2001 interactive exhibit “Brain: The World Inside Your Head” at the Smithsonian’s Arts and Industries Building in Washington. (Andrea Bruce Woodall/The Washington Post)

      The sickness spread at funerals.

    • The Fore people, a once-isolated tribe in eastern Papua New Guinea, had a long-standing tradition of mortuary feasts — eating the dead from their own community at funerals. Men consumed the flesh of their deceased relatives, while women and children ate the brain. It was an expression of respect for the lost loved ones, but the practice wreaked havoc on the communities they left behind. That’s because a deadly molecule that lives in brains was spreading to the women who ate them, causing a horrible degenerative illness called “kuru” that at one point killed 2 percent of the population each year.

      The practice was outlawed in the 1950s, and the kuru epidemic began to recede. But in its wake it left a curious and irreversible mark on the Fore, one that has implications far beyond Papua New Guinea: After years of eating brains, some Fore have developed a genetic resistance to the molecule that causes several fatal brain diseases, including kuru, mad cow disease and some cases of dementia.

      The single, protective gene is identified in a study published Wednesday in the journal Nature. Researchers say the finding is a huge step toward understanding these diseases and other degenerative brain problems, including Alzheimer’s and Parkinson’s.
      The gene works by protecting people against prions, a strange and sometimes deadly kind of protein. Though prions are naturally manufactured in all mammals, they can be deformed in a way that makes them turn on the body that made them, acting like a virus and attacking tissue. The deformed prion is even capable of infecting the prions that surround it, reshaping them to mimic its structure and its malicious ways.
      The prions’ impact on their hosts is devastating and invariably fatal. Among the Fore, the prions riddled their victims’ brains with microscopic holes, giving the organ an odd, spongy texture. In cattle, prions cause mad cow disease — they are responsible for the epidemic in Britain of the late ’80s and ’90s that required hundreds of thousands of cattle to be destroyed. They have been linked to a bizarre form of fatal insomnia that kills people by depriving them of sleep. And they’re the source of the degenerative neurological disorder Creutzfeldt-Jakob disease (CJD), characterized by rapid dementia, personality changes, muscle problems, memory loss and eventually an inability to move or speak.

      The vast majority of prion-diseases are “sporadic,” seemingly appearing without cause. But a lead author of the Nature study, John Collinge, said in an interview with Nature that a portion of cases are inherited from one’s parents, and an even smaller percentage are acquired from consuming infected tissue. Variant CJD, often called the “human mad cow disease,” is caused by eating beef from infected cows.

    • Prions are especially insidious because there’s no way of stopping them, science writer D.T. Max, author of a book on prions and fatal familial insomnia, told NPR in 2006. In the hierarchy of pathogens, they’re even more elusive and difficult to quash than a virus. They can’t be treated with antibiotics or radiation. Formalin, usually a powerful disinfectant, only makes them more virulent. The only way to clean a prion-contaminated object is with massive amounts of extremely harsh bleach, he said. But that technique isn’t helpful in treating a person who has already been infected.

    • The study by Collinge and his colleagues offers a critical insight into ways that humans might be protected from the still-little-understood prions. They found it by examining the genetic code of those families at the center of the Fore’s kuru epidemic, people who they knew had been exposed to the disease at multiple feasts, who seemed to have escaped unscathed.

      When the researchers looked at the part of the genome that encodes prion-manufacturing proteins, they found something completely unprecedented. Where humans and every other vertebrate animal in the world have an amino acid called glycine, the resistant Fore had a different amino acid, valine.

      “Several individuals right at the epicenter of the epidemic, they have this difference that we have not seen anywhere else in the world,” Collinge told Nature.

    • That minute alteration in their genome prevented the prion-producing proteins from manufacturing the disease-causing form of the molecule, protecting those individuals from kuru. To test whether it might protect them from other kinds of prion disease, Collinge — the director of a prion research unit at University College London — and his team engineered the genes of several mice to mimic that variation.

      When the scientists re-created the genetic types observed in humans — giving the mice both the normal protein and the variant in roughly equal amounts — the mice were completely resistant to kuru and to CJD. But when they looked at a second group of mice that had been genetically modified to produce only the variant protein, giving them even stronger protection, the mice were resistant to every prion strain they tested — 18 in all.
      “This is a striking example of Darwinian evolution in humans, the epidemic of prion disease selecting a single genetic change that provided complete protection against an invariably fatal dementia,” Collinge told Reuters.

    • The Fore aren’t the only people to demonstrate prion resistance. More than a decade ago, Michael Alpers — a specialist on kuru who has studied the Fore since the 1960s and was a co-author of the Nature study — conducted similar research on prion protein genes in humans worldwide. In a study published in Science, he found that people as far-flung as Europe and Japan exhibited the genetic protection, indicating that cannibalism was once widespread and that prehistoric humans probably dealt with waves of kuru-like epidemics during our evolution.

      But the gene found in the Fore is special because it seems to render mutant prion-producing proteins (the kind that would be passed down from one’s parents, causing inherited prion diseases) incapable of producing any kind of prion whatsoever. It also stops the wild-type protein — the phenotype that most people have — from making malformed prions.

    • Scientists say that the benefits of this discovery don’t stop at prion diseases, which are relatively rare — only about 300 cases are reported each year in the United States. According to Collinge, the process involved in prion diseases — prions changing the shape of the molecules around them and linking together to form long chains called “polymers” that damage the brain — is probably responsible for the deadly effects of all kinds of degenerative brain illnesses: Alzheimer’s, Parkinson’s and dementia chief among them.
      According to the World Health Organization, there are 47.5 million people worldwide living with dementia. An additional 7.7 million are diagnosed each year.

      If Collinge and his colleagues can understand the molecular mechanisms by which prions do their work — and how the prion-resistant gene stops them — they might better understand the misshapen proteins that are afflicting millions with those other degenerative brain illnesses.
      Eric Minikel, a prion researcher at the Broad Institute in Cambridge, Mass., who was not involved in the study, was impressed by the finding.
      “It is a surprise,” he told Nature. “This was a story I didn’t expect to have another chapter.”

Showing 1–20 of 20 results on a search for: kuru, fore, valine at nature.com

Internal search for the same terms turns up:

Kuru

Elevated alpha-fetoprotein
Microfold cells (or M cells)
Agrin is a large chimeric proteoglycan, a heparan sulfate and chondroitin proteoglycan, whose best-characterised role is in the development of the neuromuscular junction during embryogenesis
Lytico-bodig disease, Guam disease, or amyotrophic lateral sclerosis-parkinsonism-dementia (ALS-PDC) is a neurodegenerative disease or all of them
A selection of apothecary jars.
Columba constellation

Valine

Brain-derived neurotrophic factor (BDNF) aka abrineurin
Bacillus cereus
Elastase
Isoleucine, Tryptophol, Sleeping Sickness, The Disulfiram Effect and One Trick Hypnotists From Hell
What Is Metalloproteinase?
List of human clusters of differentiation (OR CD) MOLECULES
Waisman Article Search at NIH
Protein secondary structure
Encoded (proteinogenic) amino acids
Amino acid metabolism metabolic intermediates

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