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Cited by 213Amino Acid Enzymes and MetabolismCancer, Hypoxia, and MetabolismBacterial Cancer Therapy

The DOI matches its Crossref record; 157 of the 159 references it cites were found in a registry or an index.

The Diverse Functions of Non-Essential Amino Acids in Cancer

Open access
Choi, Bo-Hyun, Coloff, Jonathan L.·2019·Cancers
DOI 10.3390/cancers11050675PMC PMC6562791
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Abstract

Far beyond simply being 11 of the 20 amino acids needed for protein synthesis, non-essential amino acids play numerous important roles in tumor metabolism. These diverse functions include providing precursors for the biosynthesis of macromolecules, controlling redox status and antioxidant systems, and serving as substrates for post-translational and epigenetic modifications. This functional diversity has sparked great interest in targeting non-essential amino acid metabolism for cancer therapy and has motivated the development of several therapies that are either already used in the clinic or are currently in clinical trials. In this review, we will discuss the important roles that each of the 11 non-essential amino acids play in cancer, how their metabolic pathways are linked, and how researchers are working to overcome the unique challenges of targeting non-essential amino acid metabolism for cancer therapy.

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Figure 1 The interconnected pathways of non-essential amino acids (NEAA) metabolism. Glutamine and glutamate have a central role in non-essential amino acid metabolism, and can each be used for the synthesis of other NEAAs. Glutamate can be utilized to generate alanine, aspartate, serine and proline. Aspartate is further utilized to generate asparagine (with nitrogen from glutamine) and can be used in the urea cycle to make arginine. Serine donates methyl groups for one-carbon metabolism and makes glycine in the process. Serine can also be used in the transsulfuration pathway to generate cysteine. Tyrosine is the only NEAA not directly connected to the others, as it is separately synthesized from phenylalanine. Green circles indicate non-essential amino acids. Abbreviations: Gln = glutamine; Glu = glutamate; Phe = phenylalanine; Tyr = tyrosine; Ala = alanine; Pro = proline; Asp = aspartate; Asn = asparagine; Arg = arginine; Ser = serine; Gly = glycine; Met = methionine; Cys = cysteine; α-KG = α-ketoglutarate; ALT1/2 = alanine aminotransferase 1/2; AST1/2 = aspartate aminotransferase 1/2; ASNS = asparagine synthetase; ASS1 = argininosuccinate synthetase 1; ASL = argininosuccinate lyase; BCAT1/2 = branched-chain aminotransferase 1/2; GDH = glutamate dehydrogenase; GLS = glutaminase; GS = glutamine synthetase; OAA = oxaloacetate; PAH = phenylalanine hydroxylase; PHGDH = phosphoglycerate dehydrogenase; PSAT1 = phosphoserine aminotransferase 1; PSPH = phosphoserine phosphatase; P5CS = pyrroline-5-carboxylate reductase; PRODH = proline dehydrogenase; PYCR = pyrroline-5-carboxylate reductase; Pyr = pyruvate; 3-PG = 3-phosphoglycerate; 3-PHP = 3-phosphohydroxypyruvate; 3-PS = 3-phosphoserine; SHMT1/2 = serine hydroxymethyltransferase-1/2; THF = tetrahydrofolate; 5,10-mTHF = 5,10-methylenetetrahydrofolate; NH3 = ammonia.
Figure 1 The interconnected pathways of non-essential amino acids (NEAA) metabolism. Glutamine and glutamate have a central role in non-essential amino acid metabolism, and can each be used for the synthesis of other NEAAs. Glutamate can be utilized to generate alanine, aspartate, serine and proline. Aspartate is further utilized to generate asparagine (with nitrogen from glutamine) and can be used in the urea cycle to make arginine. Serine donates methyl groups for one-carbon metabolism and makes glycine in the process. Serine can also be used in the transsulfuration pathway to generate cysteine. Tyrosine is the only NEAA not directly connected to the others, as it is separately synthesized from phenylalanine. Green circles indicate non-essential amino acids. Abbreviations: Gln = glutamine; Glu = glutamate; Phe = phenylalanine; Tyr = tyrosine; Ala = alanine; Pro = proline; Asp = aspartate; Asn = asparagine; Arg = arginine; Ser = serine; Gly = glycine; Met = methionine; Cys = cysteine; α-KG = α-ketoglutarate; ALT1/2 = alanine aminotransferase 1/2; AST1/2 = aspartate aminotransferase 1/2; ASNS = asparagine synthetase; ASS1 = argininosuccinate synthetase 1; ASL = argininosuccinate lyase; BCAT1/2 = branched-chain aminotransferase 1/2; GDH = glutamate dehydrogenase; GLS = glutaminase; GS = glutamine synthetase; OAA = oxaloacetate; PAH = phenylalanine hydroxylase; PHGDH = phosphoglycerate dehydrogenase; PSAT1 = phosphoserine aminotransferase 1; PSPH = phosphoserine phosphatase; P5CS = pyrroline-5-carboxylate reductase; PRODH = proline dehydrogenase; PYCR = pyrroline-5-carboxylate reductase; Pyr = pyruvate; 3-PG = 3-phosphoglycerate; 3-PHP = 3-phosphohydroxypyruvate; 3-PS = 3-phosphoserine; SHMT1/2 = serine hydroxymethyltransferase-1/2; THF = tetrahydrofolate; 5,10-mTHF = 5,10-methylenetetrahydrofolate; NH3 = ammonia.CC BY · PubMed Central
Figure 2 The Diverse Functional Roles of NEAA in cancer. Non-essential amino acids have diverse functions in cancer cells. NADPH = Nicotinamide adenine dinucleotide phosphate.
Figure 2 The Diverse Functional Roles of NEAA in cancer. Non-essential amino acids have diverse functions in cancer cells. NADPH = Nicotinamide adenine dinucleotide phosphate.CC BY · PubMed Central

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Metadata

Authors
Choi, B.-H., & Coloff, J. L.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Coloff, Jonathan L.
ORCID
Venue
Cancers
Publisher
MDPI AG
Published
2019-05-15
Volume
11
Issue
5
Pages
675
ISSN
2072-6694 (ISSN-L)
DOI
10.3390/cancers11050675
PMC
PMC6562791
OpenAlex
W2945497873
Cited by
213
References
159
Citations by year
2026: 16 · 2025: 27 · 2024: 37 · 2023: 30 · 2022: 42 · 2021: 32 · 2020: 21 · 2019: 8
FWCI
2.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancers (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Cancer Institute (K22CA215828)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
Keywords
non-essential amino acids, cancer metabolism, amino acid biosynthesis, redox state, antioxidant defense, post-translational modification, epigenetic modifications, cancer therapy

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