DOCSLIB.ORG

Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy pharmaceuticals Review Targeting the Proline–Glutamine–Asparagine–Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy Macus Tien Kuo 1,*, Helen H. W. Chen 2, Lynn G. Feun 3 and Niramol Savaraj 4 1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 2 Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan; [email protected] 3 Department of Medicine, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; [email protected] 4 Division of Hematology and Oncology, Miami Veterans Affairs Heaithcare System, Miami, FL 33136, USA; [email protected] * Correspondence: [email protected] Abstract: Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of Citation: Kuo, M.T.; Chen, H.H.W.; compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Feun, L.G.; Savaraj, N. Targeting the Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids Proline–Glutamine–Asparagine– for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure. Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy. Keywords: amino acid starvation therapy; proline; glutamine; arginine; asparagine; drug resistance Pharmaceuticals 2021, 14, 72. https://doi.org/10.3390/ph14010072 Received: 28 December 2020 1. Introduction Accepted: 15 January 2021 Published: 18 January 2021 Amino acid starvation therapy has been emerging as an important treatment strategy in cancer therapy. This strategy is based on the promise of differential requirements of Publisher’s Note: MDPI stays neutral amino acids for supporting cell proliferation between cancer cells and normal cells. The non- with regard to jurisdictional claims in essential amino acids such as proline (Pro), glutamine (Gln), asparagine (Asn), and arginine published maps and institutional affil- (Arg) support this promise. While these amino acids can be synthesized endogenously in iations. normal cells, many human tumors, ranging from leukemia to solid cancers, do not produce sufficient amounts of these amino acids in supporting their growth. This is because the key enzymes involved in biosynthetic pathways of these amino acids are silenced. This forces tumor cells to acquire extracellular sources of amino acids to support their intracellular Copyright: © 2021 by the authors. need. Depleting these extracellular supplies result in amino acid starvation and cell death. Licensee MDPI, Basel, Switzerland. 2. The Interconnecting Proline–Glutamine–Asparagine–Arginine Metabolic Wiring in This article is an open access article Cancer Cells distributed under the terms and conditions of the Creative Commons Cells obtain amino acids from two major routes: one from the extracellular environ- Attribution (CC BY) license (https:// ment through various amino acid transporters [1] and the other from de novo biosynthesis. creativecommons.org/licenses/by/ At least 32 human solute carriers (SLC), belonging to seven families, are involved in trans- 4.0/). porting amino acids. Many of them transport multiple amino acids; likewise, multiple Pharmaceuticals 2021, 14, 72. https://doi.org/10.3390/ph14010072 https://www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2021, 14, x FOR PEER REVIEW 2 of 20 2. The Interconnecting Proline–Glutamine–Asparagine–Arginine Metabolic Wiring in Cancer Cells Cells obtain amino acids from two major routes: one from the extracellular environ- Pharmaceuticals 2021, 14, 72 ment through various amino acid transporters [1] and the other from de novo biosynthesis. 2 of 20 At least 32 human solute carriers (SLC), belonging to seven families, are involved in trans- porting amino acids. Many of them transport multiple amino acids; likewise, multiple amino acidsamino can acids be transported can be transported by the same by the SLC. same The SLC. high The redundancies high redundancies of these oftrans- these trans- porters portersin conjunction in conjunction of interconnecting of interconnecting de novo de biosynthetic novo biosynthetic processes processes of amino of acids amino acids such as suchPro, Gln, as Pro, Asn, Gln, and Asn, Arg and provide Arg provide opportunities opportunities but also but challenges also challenges for successful for successful targetedtargeted amino acid amino starvation acid starvation therapy therapy that will that be discussed will be discussed here. here. Figure 1Figure illustrates1 illustrates the interconnecting the interconnecting networks networks of amino of acids amino Pro, acids Gln, Pro, Asn, Gln, and Asn, and Arg metabolism.Arg metabolism. We place We glutamate place glutamate (Glu) in (Glu) the center in the centerof the ofnetworks. the networks. Glu is Gluthe isprod- the product uct of Glnof Glncatalyzed catalyzed by enzyme by enzyme glutaminase glutaminase (GLS) (GLS) in the in process the process known known as glutaminoly- as glutaminolysis. sis. RadiatingRadiating from from Glu are Glu the are connections the connections to (i) Pro to (i)via Pro the viapyrroline-5-carboxylate the pyrroline-5-carboxylate (P5C) (P5C) intermediate,intermediate, (ii) Arg (ii)via Argthe urea via the cycle, urea and cycle, (iii) and Asn (iii) via Asnthe aspartate via the aspartate (Asp) intermediate (Asp) intermediate catalyzedcatalyzed by glutamic by glutamic oxaloacetic oxaloacetic transaminase transaminase (GOT). (GOT). Asparagine Proline Glutamine (Gln) Glucose Asparaginase CB-839 BPTES Nucleosides Proline Glutamine Glu-6-P ProDH PYCR Asparagine GLS1 CAD Orotate P5C GS Glu Pyruvate AsnS ASNase Glutamate Citrate Gln isocitrate _ OAA Aspartate GOT GDH IDH Acetyl CoA α-Ketoglutarate Carbamoyl CS OTC ODH Phosphate ASS1 Succinyl-CoA Oxaloacetate P5C Citrulline TCA cycle (OAA) AS Ornithine Succinate NO Urea cycle MDH Polyamines SDH FH AS lyase Fumarate Malate Urea NOS Arginase Arginine Orithine + Urea Arginine Citrulline + Arginase ADI-PEG20 NH3 Figure 1. Metabolic pathways linking proline (Pro), glutamine (Glu), arginine (Arg), and asparagine Figure 1. Metabolic pathways linking proline (Pro), glutamine (Glu), arginine (Arg), and aspara- gine (Asn).(Asn). Abbreviations: Abbreviations: AS, argininosuccinate; AS, argininosuccinate; ASNase, ASNase, aspara asparaginase;ginase; AsnS, AsnS, asparagine asparagine synthe- synthetase; tase; ASS1;ASS1; argininosuccinate argininosuccinate synthetase synthetase 1; GDH, 1; GDH, glutamine glutamine dehydrogenase; dehydrogenase; glutamic-oxaloacetic glutamic-oxaloacetic transam- transaminaseinase 1; 1; FH, FH, fumarate fumarate hydratase; hydratase; GLS, GLS, glutaminase; glutaminase; GS, GS, glutamine glutamine synthetase; synthetase; GOT, GOT, glu- glutamic ox- tamic oxaloaceticaloacetic transaminase transaminase 1; 1; GDH, GDH, glutamin glutaminee dehydrogenase; dehydrogenase; NOS, NOS, nitric nitric oxide oxide synthetase; synthetase; OAA, OAA, oxaloacetate;oxaloacetate; OAT, OAT, Ornithine Ornithine aminotrans aminotransferase;ferase; OTC, OTC, ornithine ornithine transcarbamylase; transcarbamylase; P5C, P5C, pyrroline pyrroline5-carboxylate; 5-carboxylate; ProDH, ProDH, proline proline dehydrogenase; dehydrogenase; PYCR, PYCR, P5C P5C reductase. reductase. Agents Agents used used for for treatments are treatmentsunderlined are underlined and in red;and thein red; enzymes the enzymes in the pathways in the pathwa that haveys that been have considered been considered as targets as for therapies targets for therapies are boxed. CAD represents three major enzymatic steps in the biosynthesis of are boxed. CAD represents three major enzymatic steps in the biosynthesis of nucleosides from nucleosides from glutamine, i.e., carbamoyl phosphate synthetase-II (CPS-II), aspartate transcar- glutamine, i.e., carbamoyl phosphate synthetase-II (CPS-II), aspartate transcarbamylase (ATCase) bamylase (ATCase) and Dihydro orotase. and Dihydro orotase. Figure 1 also shows that starting from Pro threading through P5C, Glu, and α-ke- Figure1 also shows that starting from Pro threading through P5C, Glu, and α- toglutarate (α-KG) and fumarate (in TCA cycle) reaches Arg. Then, Arg is forward-con- ketoglutarate (α-KG) and fumarate (in TCA cycle) reaches Arg. Then, Arg is forward- verted to ornithine (Orn) catalyzed by arginase, and then to P5C by the reversible orni- converted to ornithine (Orn)
Load more

Recommended publications
  • Al Exposure Increases Proline Levels by Different Pathways in An
    www.nature.com/scientificreports OPEN Al exposure increases proline levels by diferent pathways in an Al‑sensitive and an Al‑tolerant rye genotype Alexandra de Sousa1,2, Hamada AbdElgawad2,4, Fernanda Fidalgo1, Jorge Teixeira1, Manuela Matos3, Badreldin A. Hamed4, Samy Selim5, Wael N. Hozzein6, Gerrit T. S. Beemster2 & Han Asard2* Aluminium (Al) toxicity limits crop productivity, particularly at low soil pH. Proline (Pro) plays a role in protecting plants against various abiotic stresses. Using the relatively Al‑tolerant cereal rye (Secale cereale L.), we evaluated Pro metabolism in roots and shoots of two genotypes difering in Al tolerance, var. RioDeva (sensitive) and var. Beira (tolerant). Most enzyme activities and metabolites of Pro biosynthesis were analysed. Al induced increases in Pro levels in each genotype, but the mechanisms were diferent and were also diferent between roots and shoots. The Al‑tolerant genotype accumulated highest Pro levels and this stronger increase was ascribed to simultaneous activation of the ornithine (Orn)‑biosynthetic pathway and decrease in Pro oxidation. The Orn pathway was particularly enhanced in roots. Nitrate reductase (NR) activity, N levels, and N/C ratios demonstrate that N‑metabolism is less inhibited in the Al‑tolerant line. The correlation between Pro changes and diferences in Al‑sensitivity between these two genotypes, supports a role for Pro in Al tolerance. Our results suggest that diferential responses in Pro biosynthesis may be linked to N‑availability. Understanding the role of Pro in diferences between genotypes in stress responses, could be valuable in plant selection and breeding for Al resistance. Proline (Pro) is involved in a wide range of plant physiological and developmental processes1.
    [Show full text]
  • Amino Acid Recognition by Aminoacyl-Trna Synthetases
    www.nature.com/scientificreports OPEN The structural basis of the genetic code: amino acid recognition by aminoacyl‑tRNA synthetases Florian Kaiser1,2,4*, Sarah Krautwurst3,4, Sebastian Salentin1, V. Joachim Haupt1,2, Christoph Leberecht3, Sebastian Bittrich3, Dirk Labudde3 & Michael Schroeder1 Storage and directed transfer of information is the key requirement for the development of life. Yet any information stored on our genes is useless without its correct interpretation. The genetic code defnes the rule set to decode this information. Aminoacyl-tRNA synthetases are at the heart of this process. We extensively characterize how these enzymes distinguish all natural amino acids based on the computational analysis of crystallographic structure data. The results of this meta-analysis show that the correct read-out of genetic information is a delicate interplay between the composition of the binding site, non-covalent interactions, error correction mechanisms, and steric efects. One of the most profound open questions in biology is how the genetic code was established. While proteins are encoded by nucleic acid blueprints, decoding this information in turn requires proteins. Te emergence of this self-referencing system poses a chicken-or-egg dilemma and its origin is still heavily debated 1,2. Aminoacyl-tRNA synthetases (aaRSs) implement the correct assignment of amino acids to their codons and are thus inherently connected to the emergence of genetic coding. Tese enzymes link tRNA molecules with their amino acid cargo and are consequently vital for protein biosynthesis. Beside the correct recognition of tRNA features3, highly specifc non-covalent interactions in the binding sites of aaRSs are required to correctly detect the designated amino acid4–7 and to prevent errors in biosynthesis5,8.
    [Show full text]
  • Asparagine-Proline Sequence Within Membrane-Spanning Segment of SREBP Triggers Intramembrane Cleavage by Site-2 Protease
    Asparagine-proline sequence within membrane-spanning segment of SREBP triggers intramembrane cleavage by Site-2 protease Jin Ye*†, Utpal P. Dave´ *†, Nick V. Grishin‡, Joseph L. Goldstein*§, and Michael S. Brown*§ Departments of *Molecular Genetics and ‡Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046 Contributed by Joseph L. Goldstein, March 16, 2000 The NH2-terminal domains of membrane-bound sterol regulatory nus. It translocates to the nucleus, where it activates more than element-binding proteins (SREBPs) are released into the cytosol by 20 genes encoding enzymes of cholesterol and fatty acid synthesis regulated intramembrane proteolysis, after which they enter the as well as the low density lipoprotein receptor (6, 7). When nucleus to activate genes encoding lipid biosynthetic enzymes. sterols build up in cells, the SREBP͞SCAP complex fails to exit Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a the ER, and it never reaches S1P (8, 9). As a result, the hydrophobic zinc metalloprotease that cleaves SREBPs at a mem- NH2-terminal domains of the SREBPs are no longer released brane-embedded leucine-cysteine bond. In the current study, we into the nucleus, and transcription of the target genes declines. use domain-swapping methods to localize the residues within This mechanism allows cholesterol to inhibit its own synthesis the SREBP-2 membrane-spanning segment that are required for and uptake, thereby preventing cholesterol overaccumulation in cleavage by S2P. The studies reveal a requirement for an asparag- cells. ine-proline sequence in the middle third of the transmembrane The human gene encoding S2P was cloned by complementa- segment.
    [Show full text]
  • Low Proline Diet in Type I Hyperprolinaemia
    Arch Dis Child: first published as 10.1136/adc.46.245.72 on 1 February 1971. Downloaded from Archives of Disease in Childhood, 1971, 46, 72. Low Proline Diet in Type I Hyperprolinaemia J. T. HARRIES, A. T. PIESOWICZ,* J. W. T. SEAKINS, D. E. M. FRANCIS, and 0. H. WOLFF From The Hospital for Sick Children, and the Institute of Child Health, University of London Harries, J. T., Piesowicz, A. T., Seakins, J. W. T., Francis, D. E. M., and Wolff, 0. H. (1971). Archives of Disease in Childhood, 46, 72. Low proline diet in type I hyperprolinaemia. A diagnosis of Type I hyperprolinaemia was made in a 7-month-old infant who presented with hypocalcaemic convulsions and malabsorp- tion. The plasma levels of proline were grossly raised and the urinary excretion of proline, hydroxyproline, and glycine was increased; neurological development was delayed and there were associated abnormalities of the electroencephalogram, renal tract, and bones. Restriction of dietary proline at the age of 9 months resulted in a prompt fall of plasma levels of proline to normal, and a low proline diet was continued until the age of 27 months when persistence of the biochemical defect was shown. During the period of dietary treatment, growth was satisfactory, mental development improved, and the electroencephalogram, and the renal, skeletal, and intestinal abnormalities disappeared. Proline should be regarded as a 'semi-essential' amino acid in the growing infant. Hyperprolinaemia, appearing in several members balance can be maintained on a proline-free diet copyright. of a family was first described by Scriver, Schafer, (Rose et al., 1955), and therefore the amino acid is and Efron in 1961.
    [Show full text]
  • Amino Acid Chemistry
    Handout 4 Amino Acid and Protein Chemistry ANSC 619 PHYSIOLOGICAL CHEMISTRY OF LIVESTOCK SPECIES Amino Acid Chemistry I. Chemistry of amino acids A. General amino acid structure + HN3- 1. All amino acids are carboxylic acids, i.e., they have a –COOH group at the #1 carbon. 2. All amino acids contain an amino group at the #2 carbon (may amino acids have a second amino group). 3. All amino acids are zwitterions – they contain both positive and negative charges at physiological pH. II. Essential and nonessential amino acids A. Nonessential amino acids: can make the carbon skeleton 1. From glycolysis. 2. From the TCA cycle. B. Nonessential if it can be made from an essential amino acid. 1. Amino acid "sparing". 2. May still be essential under some conditions. C. Essential amino acids 1. Branched chain amino acids (isoleucine, leucine and valine) 2. Lysine 3. Methionine 4. Phenyalanine 5. Threonine 6. Tryptophan 1 Handout 4 Amino Acid and Protein Chemistry D. Essential during rapid growth or for optimal health 1. Arginine 2. Histidine E. Nonessential amino acids 1. Alanine (from pyruvate) 2. Aspartate, asparagine (from oxaloacetate) 3. Cysteine (from serine and methionine) 4. Glutamate, glutamine (from α-ketoglutarate) 5. Glycine (from serine) 6. Proline (from glutamate) 7. Serine (from 3-phosphoglycerate) 8. Tyrosine (from phenylalanine) E. Nonessential and not required for protein synthesis 1. Hydroxyproline (made postranslationally from proline) 2. Hydroxylysine (made postranslationally from lysine) III. Acidic, basic, polar, and hydrophobic amino acids A. Acidic amino acids: amino acids that can donate a hydrogen ion (proton) and thereby decrease pH in an aqueous solution 1.
    [Show full text]
  • Amino Acids Amino Acids
    Amino Acids Amino Acids What Are Amino Acids? Essential Amino Acids Non Essential Amino Acids Amino acids are the building blocks of proteins; proteins are made of amino acids. Isoleucine Arginine (conditional) When you ingest a protein your body breaks it down into the individual aminos, Leucine Glutamine (conditional) reorders them, re-folds them, and turns them into whatever is needed by the body at Lysine Tyrosine (conditional) that time. From only 20 amino acids, the body is able to make thousands of unique proteins with different functions. Methionine Cysteine (conditional) Phenylalanine Glycine (conditional) Threonine Proline (conditional) Did You Know? Tryptophan Serine (conditional) Valine Ornithine (conditional) There are 20 different types of amino acids that can be combined to make a protein. Each protein consists of 50 to 2,000 amino acids that are connected together in a specific Histidine* Alanine sequence. The sequence of the amino acids determines each protein’s unique structure Asparagine and its specific function in the body. Asparate Popular Amino Acid Supplements How Do They Benefit Our Health? Acetyl L- Carnitine: As part of its role in supporting L-Lysine: L-Lysine, an essential amino acid, is mental function, Acetyl L-Carnitine may help needed to support proper growth and bone Proteins (amino acids) are needed by your body to maintain muscles, bones, blood, as support memory, attention span and mental development. It can also support immune function. well as create enzymes, neurotransmitters and antibodies, as well as transport and performance. store molecules. N-Acetyl Cysteine: N-Acetyl Cysteine (NAC) is a L-Arginine: L-Arginine is a nonessential amino acid form of the amino acid cysteine.
    [Show full text]
  • Proline Oxidase Controls Proline, Glutamate, and Glutamine Cellular Concentrations in a U87 Glioblastoma Cell Line
    RESEARCH ARTICLE Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line Pamela Cappelletti1,2*, Elena Tallarita1, Valentina Rabattoni1, Paola Campomenosi1,2, Silvia Sacchi1,2, Loredano Pollegioni1,2 1 Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy, 2 The Protein Factory Research Center, Politecnico of Milano and University of Insubria, Milano, Italy a1111111111 * [email protected] a1111111111 a1111111111 a1111111111 a1111111111 Abstract L-Proline is a multifunctional amino acid that plays an essential role in primary metabolism and physiological functions. Proline is oxidized to glutamate in the mitochondria and the FAD-containing enzyme proline oxidase (PO) catalyzes the first step in L-proline degrada- OPEN ACCESS tion pathway. Alterations in proline metabolism have been described in various human dis- Citation: Cappelletti P, Tallarita E, Rabattoni V, eases, such as hyperprolinemia type I, velo-cardio-facial syndrome/Di George syndrome, Campomenosi P, Sacchi S, Pollegioni L (2018) schizophrenia and cancer. In particular, the mutation giving rise to the substitution Leu441- Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 Pro was identified in patients suffering of schizophrenia and hyperprolinemia type I. Here, glioblastoma cell line. PLoS ONE 13(4): e0196283. we report on the expression of wild-type and L441P variants of human PO in a U87 glioblas- https://doi.org/10.1371/journal.pone.0196283 toma human cell line in an attempt to assess their effect on glutamate metabolism. The sub- Editor: Suzie Chen, Rutgers University, UNITED cellular localization of the flavoenzyme is not altered in the L441P variant, for which specific STATES activity is halved compared to the wild-type PO.
    [Show full text]
  • Nucleotide Base Coding and Am1ino Acid Replacemients in Proteins* by Emil L
    VOL. 48, 1962 BIOCHEMISTRY: E. L. SAIITH 677 18 Britten, R. J., and R. B. Roberts, Science, 131, 32 (1960). '9 Crestfield, A. M., K. C. Smith, and F. WV. Allen, J. Biol. Chem., 216, 185 (1955). 20 Gamow, G., Nature, 173, 318 (1954). 21 Brenner, S., these PROCEEDINGS, 43, 687 (1957). 22 Nirenberg, M. WV., J. H. Matthaei, and 0. WV. Jones, unpublished data. 23 Crick, F. H. C., L. Barnett, S. Brenner, and R. J. Watts-Tobin, Nature, 192, 1227 (1961). 24 Levene, P. A., and R. S. Tipson, J. Biol. Ch-nn., 111, 313 (1935). 25 Gierer, A., and K. W. Mundry, Nature, 182, 1437 (1958). 2' Tsugita, A., and H. Fraenkel-Conrat, J. Mllot. Biol., in press. 27 Tsugita, A., and H. Fraenkel-Conrat, personal communication. 28 Wittmann, H. G., Naturwissenschaften, 48, 729 (1961). 29 Freese, E., in Structure and Function of Genetic Elements, Brookhaven Symposia in Biology, no. 12 (1959), p. 63. NUCLEOTIDE BASE CODING AND AM1INO ACID REPLACEMIENTS IN PROTEINS* BY EMIL L. SMITHt LABORATORY FOR STUDY OF HEREDITARY AND METABOLIC DISORDERS AND THE DEPARTMENTS OF BIOLOGICAL CHEMISTRY AND MEDICINE, UNIVERSITY OF UTAH COLLEGE OF MEDICINE Communicated by Severo Ochoa, February 14, 1962 The problem of which bases of messenger or template RNA' specify the coding of amino acids in proteins has been largely elucidated by the use of synthetic polyri- bonucleotides.2-7 For these triplet nucleotide compositions (Table 1), it is of in- terest to examine some of the presently known cases of amino acid substitutions in polypeptides or proteins of known structure.
    [Show full text]
  • Table 2 Amino Acid Sequence of OC-17 As Taken from Ref. 28 Amino
    Electronic Supplementary Material (ESI) for Physical Chemistry Chemical Physics This journal is © The Owner Societies 2012 Table 2 Amino Acid Sequence of OC-17 as taken from ref. 28 Amino Acid Abbr. Sequence Position Amino Acid Abbr. Sequence Position Amino Acid Abbr. Sequence Position Aspartic Acid ASP 1 Alanine ALA 49 Arginine ARG 97 Proline PRO 2 Glutamic Acid GLU 50 Phenyalanine PHE 98 Aspartic Acid ASP 3 Leucine LEU 51 Alanine ALA 99 Glycine GLY 4 Arginine ARG 52 Serine SER 100 Cysteine CYS 5 Leucine LEU 53 Tryptophan TRP 101 Glycine GLY 6 Leucine LEU 54 Histidine HIE 102 Proline PRO 7 Alanine ALA 55 Arginine ARG 103 Glycine GLY 8 Glutamic Acid GLU 56 Threonine THR 104 Tryptophan TRP 9 Leucine LEU 57 Alanine ALA 105 Valine VAL 10 Leucine LEU 58 Lysine LYS 106 Proline PRO 11 Asparagine ASN 59 Alanine ALA 107 Threonine THR 12 Alanine ALA 60 Arginine ARG 108 Proline PRO 13 Serine SER 61 Arginine ARG 109 Glycine GLY 14 Arginine ARG 62 Glycine GLY 110 Glycine GLY 15 Glycine GLY 63 Glycine GLY 111 Cysteine CYS 16 Glycine GLY 64 Arginine ARG 112 Leucine LEU 17 Aspartic Acid ASP 65 Cysteine CYS 113 Glycine GLY 18 Glycine GLY 66 Alanine ALA 114 Phenyalanine PHE 19 Serine SER 67 Alanine ALA 115 Phenyalanine PHE 20 Glycine GLY 68 Leucine LEU 116 Serine SER 21 Glutamic Acid GLU 69 Arginine ARG 117 Arginine ARG 22 Glycine GLY 70 Aspartic Acid ASP 118 Glutamic Acid GLU 23 Alanine ALA 71 Glutamic Acid GLU 119 Leucine LEU 24 Aspartic Acid ASP 72 Glutamic Acid GLU 120 Serine SER 25 Glycine GLY 73 Alanine ALA 121 Tryptophan TRP 26 Arginine ARG 74 Phenyalanine
    [Show full text]
  • An Integrated Meta-Analysis of Peripheral Blood Metabolites and Biological Functions in Major Depressive Disorder
    Molecular Psychiatry https://doi.org/10.1038/s41380-020-0645-4 ARTICLE An integrated meta-analysis of peripheral blood metabolites and biological functions in major depressive disorder 1,2,3 1,2,3 1,2,3 1,3 1,3 4,5 1,3 1,3 Juncai Pu ● Yiyun Liu ● Hanping Zhang ● Lu Tian ● Siwen Gui ● Yue Yu ● Xiang Chen ● Yue Chen ● 1,2,3 1,3 1,3 1,3 1,3 1,2,3 Lining Yang ● Yanqin Ran ● Xiaogang Zhong ● Shaohua Xu ● Xuemian Song ● Lanxiang Liu ● 1,2,3 1,3 1,2,3 Peng Zheng ● Haiyang Wang ● Peng Xie Received: 3 June 2019 / Revised: 24 December 2019 / Accepted: 10 January 2020 © The Author(s) 2020. This article is published with open access Abstract Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially 1234567890();,: 1234567890();,: expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenode- soxycholic acid and lower levels of L-acetylcarnitine, creatinine, L-asparagine, L-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, L-serine, oleic acid, myo-inositol, dodecanoic acid, L-methionine, hypoxanthine, palmitic acid, L-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls.
    [Show full text]
  • The Fate of Arginine and Proline Carbon in Squid Tissuesl
    Pacific Science (1982), vol. 36, no. 3 © 1983 by the University of Hawaii Press. All rights reserved The Fate of Arginine and Proline Carbon in Squid Tissuesl T. P. MOMMSEN,2 C. J. FRENCH,2 B. EMMETI,2 and P. W. HOCHACHKA2 ABSTRACT: The metabolism of proline and arginine was investigated in kidney, gill, and heart of the pelagic squid, Symplectoteuthis. The rates of CO2 release from 14C-proline exceeded the rates from 14C-arginine. The metabolic rate of arginine and proline was assessed by monitoring the incorporation of arginine-derived carbon into various intermediates. Arginine was metabolized, through ornithine, to proline as well as to glutamate and various subsequent derivatives (alanine, octopine, aspartate, and carboxylic acids). The same com­ ponents became labeled using 14C-proline as the starting substrate, but only the gill was capable ofconverting proline to arginine via the urea cycle. In addition, 14C-proline oxidation rates were high enough to exceed those of 14C-glucose in at least three tissues, kidney, heart, and inner mantle muscle. AT LEAST IN PART because ofthe large pool size data for heart, gill, and kidney from the squid, of free amino acids in cephalopod muscles Symplectoteuthis, showing the capacity for ar­ (e.g., see Hochachka, French, and Meredith ginine conversion to proline. The conversion 1978), interest recently has been focusing ofproline to arginine was measurable only in on their possible roles in energy metabolism. the gill. Although qualitatively similar to re­ During metabolic studies on the 1979 Alpha sults obtained with other species, these data Helix Cephalopod Expedition, relatively high also show some important, tissue-specific dif­ rates of CO2 release from arginine and ferences (Mommsen et al.
    [Show full text]
  • Arginine Is Synthesized from Proline, Not Glutamate, in Enterally Fed Human Preterm Neonates
    0031-3998/11/6901-0046 Vol. 69, No. 1, 2011 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2010 International Pediatric Research Foundation, Inc. Arginine Is Synthesized From Proline, Not Glutamate, in Enterally Fed Human Preterm Neonates CHRIS TOMLINSON, MAHROUKH RAFII, MICHAEL SGRO, RONALD O. BALL, AND PAUL PENCHARZ Department of Paediatrics [C.T., M.S., P.P.], Research Institute [C.T., M.R., P.P.], The Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada; Department of Nutritional Sciences [C.T., M.S., P.P.], University of Toronto, Toronto, Ontario M5S3E2, Canada; Department of Paediatrics [M.S.], St Michael’s Hospital, Toronto, Ontario M5B1W8, Canada; Department of Agricultural, Food and Nutritional Science [R.O.B., P.P.], University of Alberta, Edmonton, Alberta T6G2P5, Canada ABSTRACT: In neonatal mammals, arginine is synthesized in the litis (NEC) (8) and pulmonary hypertension (9). Furthermore, enterocyte, with either proline or glutamate as the dietary precursor. arginine supplementation was shown to reduce the incidence We have shown several times in piglets that proline is the only of all stages of NEC in moderately at risk infants (10) and a precursor to arginine, although in vitro evidence supports glutamate single bolus infusion of i.v. arginine improved oxygenation in in this role. Because of this uncertainty, we performed a multitracer infants with pulmonary hypertension (11). Therefore, because stable isotope study to determine whether proline, glutamate, or both are dietary precursors for arginine in enterally fed human neonates. arginine is clearly important for metabolism in the neonate, it Labeled arginine (M ϩ 2), proline (M ϩ 1), and glutamate (M ϩ 3) is critical to understand the metabolic pathways involved in its were given enterally to 15 stable, growing preterm infants (GA at synthesis.
    [Show full text]