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Metabolic Basis of Creatine in Health and Disease: a Bioinformatics-Assisted Review

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Metabolic Basis of Creatine in Health and Disease: a Bioinformatics-Assisted Review nutrients Review Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review Diego A. Bonilla 1,2,3,4,* , Richard B. Kreider 5 , Jeffrey R. Stout 6 , Diego A. Forero 7, Chad M. Kerksick 8 , Michael D. Roberts 9,10 and Eric S. Rawson 11 1 Research Division, Dynamical Business & Science Society–DBSS International SAS, Bogotá 110861, Colombia 2 Research Group in Biochemistry and Molecular Biology, Universidad Distrital Francisco José de Caldas, Bogotá 110311, Colombia 3 Research Group in Physical Activity, Sports and Health Sciences (GICAFS), Universidad de Córdoba, Montería 230002, Colombia 4 kDNA Genomics®, Joxe Mari Korta Research Center, University of the Basque Country UPV/EHU, 20018 Donostia-San Sebastián, Spain 5 Exercise & Sport Nutrition Laboratory, Human Clinical Research Facility, Texas A&M University, College Station, TX 77843, USA; [email protected] 6 Physiology of Work and Exercise Response (POWER) Laboratory, Institute of Exercise Physiology and Rehabilitation Science, University of Central Florida, Orlando, FL 32816, USA; [email protected] 7 Professional Program in Sport Training, School of Health and Sport Sciences, Fundación Universitaria del Área Andina, Bogotá 111221, Colombia; [email protected] 8 Exercise and Performance Nutrition Laboratory, School of Health Sciences, Lindenwood University, Saint Charles, MO 63301, USA; [email protected] 9 School of Kinesiology, Auburn University, Auburn, AL 36849, USA; [email protected] 10 Edward via College of Osteopathic Medicine, Auburn, AL 36849, USA 11 Department of Health, Nutrition and Exercise Science, Messiah University, Mechanicsburg, PA 17055, USA; [email protected] Citation: Bonilla, D.A.; Kreider, R.B.; * Correspondence: [email protected]; Tel.: +57-320-335-2050 Stout, J.R.; Forero, D.A.; Kerksick, C.M.; Roberts, M.D.; Rawson, E.S. Abstract: Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and Metabolic Basis of Creatine in Health pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells and Disease: A Bioinformatics- through a specific symporter called Na+/Cl−-dependent Cr transporter (CRT). Once within cells, Assisted Review. Nutrients 2021, 13, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4−]2− 1238. https://doi.org/10.3390/ 2+ 3− − nu13041238 and Cr to produce phosphocreatine (PCr) and [Mg :ADP ] . We aimed to perform a comprehen- sive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Academic Editor: Susanne Klaus Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were Received: 23 March 2021 addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) Accepted: 7 April 2021 What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in Published: 9 April 2021 cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Publisher’s Note: MDPI stays neutral Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell with regard to jurisdictional claims in survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary published maps and institutional affil- advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. iations. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Keywords: creatine kinase; energy metabolism; cell survival; bioinformatics; systems biology; cellular This article is an open access article allostasis; dynamic biosensor distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Nutrients 2021, 13, 1238. https://doi.org/10.3390/nu13041238 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 36 Nutrients 2021, 13, 1238 2 of 32 1. Introduction 1. Introduction Creatine (Cr) is a ubiquitous non-protein amino acid (PubChem CID: 586) that is syn- Creatine (Cr) is a ubiquitous non-protein amino acid (PubChem CID: 586) that is thesized mainly in the liver, kidneys, and pancreas [1]. However, other tissues (e.g., brain synthesized mainly in the liver, kidneys, and pancreas [1]. However, other tissues (e.g., and testes) are also able to produce Cr [2–4]. Endogenous Cr synthesis begins with the brain and testes) are also able to produce Cr [2–4]. Endogenous Cr synthesis begins with the transfer of the amidino group of L-arginine to the Nα-amine group of L-glycine following transfer of the amidino group of L-arginine to the Nα-amine group of L-glycine following a a ping-pong mechanism that is catalyzed by L-Arginine-Glycine amidinotransferase ping-pong mechanism that is catalyzed by L-Arginine-Glycine amidinotransferase (AGAT- (AGAT-EC 2.1.4.1)EC2.1.4.1) [5]. This [5 first]. This reaction first reaction yields L-ornithine yields L-ornithine and guanidinoacetate and guanidinoacetate (GAA), (GAA), which which is then methylatedis then methylated at the original at the originalnitrogen nitrogen of glycine of glycineusing S-adenosyl-L-methio- using S-adenosyl-L-methionine as nine as the donorthe of donor the methyl of the group methyl by group means by of means the Guanidinoacetate of the Guanidinoacetate N-Methyltrans- N-Methyltransferase ferase (GAMT-EC(GAMT-EC 2.1.1.2). This 2.1.1.2). reaction This foll reactionows the follows formation the formationof a strong of nucleophile a strong nucleophile on on the the deprotonateddeprotonated glycine-derived glycine-derived N of GAA Nthat of interacts GAA that with interacts the methyl with thegroup methyl from group from the the positively chargedpositively sulfonium charged ion sulfonium of S-adenosyl-L-methionine ion of S-adenosyl-L-methionine [6] to produce [6] Cr to produceand Cr and S- S-adenosyl-L-cysteineadenosyl-L-cysteine (Figure 1). (Figure1). Figure 1. CreatineFigure synthesis/excretion1. Creatine synthesis/excretion and the creatine and the kinase creatine reaction. kinase Enzymes reaction. are Enzymes represented are byrepresented ovals. Once by synthesized from L-arginine,ovals. glycine, Once synthesized and S-adenosyl-L-methionine, from L-arginine, glycine, creatine and (Cr) S-adenosyl-L-m is converted toethionine, phosphocreatine creatine (Cr) (PCr) is bycon- means of the 2− 3− creatine kinaseverted (CK), to phosphocreatine which catalyzes the(PCr) reversible by means transference of the creatine of a kinase phosphoryl (CK), groupwhich (POcatalyzes3 ), notthe areversible phosphate (PO4 ), 2- 3- from ATP. Thetransference kinetic rate of ofa phosphoryl the non-enzymatic group (PO conversion3 ), not ofa phosphate Cr (or PCr) (PO to creatinine4 ), from ATP. (Crn) The depends kinetic on rate the Hof+ concentra- + tion of the media.the non-enzymatic It is important conversion to note thatof Cr neither (or PC Crnr) to norcreatinine PCr are (Crn) substrates depends of theon the sodium- H concentration and chloride-dependent of the media. It is important to note that neither Crn nor PCr are substrates of the sodium- and chlo- creatine transporter (not shown). Oval size represents the expression level of AGAT (black), GAMT (white), and CK (orange) ride-dependent creatine transporter (not shown). Oval size represents the expression level of AGAT in some tissues. For more details related to expression in different tissues or conditions (i.e., pathologies) use the following (black), GAMT (white), and CK (orange) in some tissues. For more details related to expression in BioGPS IDdifferent numbers: tissues AGAT–2628; or conditions GAMT–2593. (i.e., pathologies) AGAT: L-Arginine-Glycine use the following amidinotransferase; BioGPS ID numbers: GAMT: AGAT–2628; Guanidinoacetate + N-Methyltransferase;GAMT–2593. H AGAT:: hydrogen L-Arginine-Glycine ion; Pi: inorganic amidinotra phosphate.nsferase; Modified GAMT: with permissionGuanidinoacetate from Bonilla N-Methyl- and Moreno [7] using the Freewaretransferase; ACD/ChemSketch H+: hydrogen ion; 2021 Pi: (Advancedinorganic phosphate. Chemistry Mo Development,dified with permission Inc., Toronto, from ON, Bonilla Canada). and Nutrients 2021, 13, 1238 3 of 32 High Cr concentrations are found in skeletal muscle and the brain [8]. High Cr levels are also found in other cells with high energy demands such as the cardiomyocytes, hepatocytes, kidney cells, inner ear cells, enterocytes, spermatozoa, and photoreceptor cells [9,10]. However, approximately 95% of the Cr pool in the body is found in skeletal muscle [11–13]. After synthesis, Cr reaches target tissues through the bloodstream, and intracellular transport mediated by a solute carrier protein called sodium- and chloride- dependent creatine transporter (CRT, also known as SLC6A8) [14]. This symporter belongs to a family of neurotransmitter transporters known as solute carrier family 6, which
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