T3DB: Guanidinosuccinic acid

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (3)XML

Targets (3)

Record Information

Version

2.0

Creation Date

2014-08-29 05:49:30 UTC

Update Date

2014-12-24 20:26:41 UTC

Accession Number

T3D4174

Identification

Common Name

Guanidinosuccinic acid

Class

Small Molecule

Description

Guanidinosuccinic acid is a uremic toxin. Uremic toxins can be subdivided into three major groups based upon their chemical and physical characteristics: 1) small, water-soluble, non-protein-bound compounds, such as urea; 2) small, lipid-soluble and/or protein-bound compounds, such as the phenols and 3) larger so-called middle-molecules, such as beta2-microglobulin. Chronic exposure of uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease. Guanidinosuccinic acid (GSA) is one of the earliest uremic toxins isolated and its toxicity identified. Its metabolic origins show that it arose from the oxidation of argininosuccinic acid (ASA) by free radicals. The stimulus for this oxidation, occurring optimally in the presence of the failed kidney, is the rising level of urea which, through enzyme inhibition, results in a decline in hepatic levels of the semi-essential amino acid, arginine. It is further noted that concentrations of GSA in both serum and urine decline sharply in animals and humans exposed to the essential amino acid, methionine. Uremic patients suffer from a defective ability to generate methyl groups due to anorexia, dietary restrictions and renal protein leakage. This leads to the accumulation of homocysteine, a substance known to produce vascular damage. Even in healthy subjects intake of choline together with methionine is insufficient to satisfy total metabolic requirements for methyl groups. In end-stage renal disease, therefore, protein restriction contributes to the build-up of toxins in uremia. Replacement using specific amino acid mixtures should be directed toward identified deficiencies and adequacy monitored by following serum levels of the related toxins, in this case GSA and homocysteine. (1).

Compound Type

Amide
Amine
Food Toxin
Metabolite
Natural Compound
Organic Compound
Uremic Toxin

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

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Chemical Formula

C₅H₉N₃O₄

Average Molecular Mass

175.143 g/mol

Monoisotopic Mass

175.059 g/mol

CAS Registry Number

6133-30-8

IUPAC Name

(2S)-2-carbamimidamidobutanedioic acid

Traditional Name

N-amidino-L-aspartic acid

SMILES

[H][C@@](CC(O)=O)(NC(N)=N)C(O)=O

InChI Identifier

InChI=1S/C5H9N3O4/c6-5(7)8-2(4(11)12)1-3(9)10/h2H,1H2,(H,9,10)(H,11,12)(H4,6,7,8)/t2-/m0/s1

InChI Key

InChIKey=VVHOUVWJCQOYGG-REOHCLBHSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as aspartic acid and derivatives. Aspartic acid and derivatives are compounds containing an aspartic acid or a derivative thereof resulting from reaction of aspartic acid at the amino group or the carboxy group, or from the replacement of any hydrogen of glycine by a heteroatom.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Carboxylic acids and derivatives

Sub Class

Amino acids, peptides, and analogues

Direct Parent

Aspartic acid and derivatives

Alternative Parents

Substituents

Aspartic acid or derivatives
Dicarboxylic acid or derivatives
Fatty acid
Guanidine
Organic 1,3-dipolar compound
Propargyl-type 1,3-dipolar organic compound
Carboximidamide
Carboxylic acid
Organopnictogen compound
Hydrocarbon derivative
Organic oxygen compound
Organooxygen compound
Organonitrogen compound
Organic nitrogen compound
Carbonyl group
Organic oxide
Aliphatic acyclic compound

Molecular Framework

Aliphatic acyclic compounds

External Descriptors

guanidines (CHEBI:17072 )
C4-dicarboxylic acid (CHEBI:17072 )
L-aspartic acid derivative (CHEBI:17072 )
N-amidino-amino acid (CHEBI:17072 )

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

White powder.

Experimental Properties

Property	Value
Melting Point	Not Available
Boiling Point	Not Available
Solubility	Not Available
LogP	-2.068

Predicted Properties

Property	Value	Source
Water Solubility	2.82 g/L	ALOGPS
logP	-1.6	ALOGPS
logP	-3.3	ChemAxon
logS	-1.8	ALOGPS
pKa (Strongest Acidic)	2.98	ChemAxon
pKa (Strongest Basic)	12.23	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	7	ChemAxon
Hydrogen Donor Count	5	ChemAxon
Polar Surface Area	136.5 Å²	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	47.25 m³·mol⁻¹	ChemAxon
Polarizability	15.13 Å³	ChemAxon
Number of Rings	0	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-000x-9600000000-6898be602fa231388ab5	2017-09-01	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (2 TMS) - 70eV, Positive	splash10-00di-9282000000-37ec05543d3d8d30ad15	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-004i-1900000000-466615ceb5129f085333	2012-07-25	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-00di-9000000000-e5868bbf32c1407fa030	2012-07-25	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-006x-9000000000-f34cd801b9c1e714a6fc	2012-07-25	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Negative	splash10-000i-9200000000-2cad41f1508b5f26c3a4	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0079-9100000000-05168c0ae4e3fdabfb73	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-004i-3900000000-df5df4302173fb4e9d29	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Negative	splash10-001r-5900000000-a31472885115c0129885	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9000000000-36781515ea42c79fcca5	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-005i-5900000000-37fe8d8d0c84140e147c	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9000000000-ba089dcdaa7d9545ac43	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Negative	splash10-005i-2900000000-d58d2731ca71e2359e24	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Positive	splash10-005i-3900000000-e366d1ed9f73879bd47f	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Positive	splash10-0006-9000000000-49e8a9df2b750e494685	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Negative	splash10-0a4r-9000000000-948b748bb9ac50e676a1	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-00dr-9100000000-ac4c3bddfe7b0a568fff	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-004i-2900000000-e7544c898162e6c51b54	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Positive	splash10-004i-3900000000-f755abe1d2fcfc810e3f	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Positive	splash10-0079-9200000000-78e26e891d49a63dc6b6	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-0a4i-0900000000-766bed5b22ec642474b7	2017-09-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-090r-6900000000-c59abb9d78dd85396ad9	2017-09-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-03di-9000000000-809ece24ff681a989230	2017-09-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-0089-1900000000-ab305bd5f1306019d2bb	2017-09-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-0a5i-9500000000-e46a9bb7a8167700416d	2017-09-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-0006-9000000000-cf381fa0309c6e1df17d	2017-09-01	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-02a9-6900000000-3e4021155970f30bc06c	2021-09-23	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, H₂O, experimental)	Not Available	2012-12-05	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-25	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, H₂O, experimental)	Not Available	2021-10-10	View Spectrum
2D NMR	[¹H, ¹³C]-HSQC NMR Spectrum (2D, 600 MHz, H₂O, experimental)	Not Available	2012-12-05	View Spectrum

Toxicity Profile

Route of Exposure

Endogenous, Ingestion, Dermal (contact)

Mechanism of Toxicity

Uremic toxins such as guanidinosuccinic acid are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (3). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (4).

Metabolism

Uremic toxins tend to accumulate in the blood either through dietary excess or through poor filtration by the kidneys. Most uremic toxins are metabolic waste products and are normally excreted in the urine or feces.

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Naturally produced by the body (endogenous).

Minimum Risk Level

Not Available

Health Effects

Chronic exposure to uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.

Symptoms

As a uremic toxin, this compound can cause uremic syndrome. Uremic syndrome may affect any part of the body and can cause nausea, vomiting, loss of appetite, and weight loss. It can also cause changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma. Abnormal bleeding, such as bleeding spontaneously or profusely from a very minor injury can also occur. Heart problems, such as an irregular heartbeat, inflammation in the sac that surrounds the heart (pericarditis), and increased pressure on the heart can be seen in patients with uremic syndrome. Shortness of breath from fluid buildup in the space between the lungs and the chest wall (pleural effusion) can also be present.

Treatment

Kidney dialysis is usually needed to relieve the symptoms of uremic syndrome until normal kidney function can be restored.

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

Not Available

HMDB ID

HMDB03157

PubChem Compound ID

439918

ChEMBL ID

Not Available

ChemSpider ID

388951

KEGG ID

C03139

UniProt ID

Not Available

OMIM ID

ChEBI ID

17072

BioCyc ID

CPD-599

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Not Available

References

Synthesis Reference

Not Available

MSDS

Link

General References

Cohen BD: Methyl group deficiency and guanidino production in uremia. Mol Cell Biochem. 2003 Feb;244(1-2):31-6. [12701806 ]
Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A: Normal and pathologic concentrations of uremic toxins. J Am Soc Nephrol. 2012 Jul;23(7):1258-70. doi: 10.1681/ASN.2011121175. Epub 2012 May 24. [22626821 ]
Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]
Torremans A, Marescau B, Van Dam D, Van Ginneken C, Van Meir F, Van Bogaert PP, D'Hooge R, de Vente J, De Deyn PP: GSA: behavioral, histological, electrophysiological and neurochemical effects. Physiol Behav. 2005 Feb 15;84(2):251-64. Epub 2005 Jan 8. [15708777 ]
Mizutani N, Hayakawa C, Ohya Y, Watanabe K, Watanabe Y, Mori A: Guanidino compounds in hyperargininemia. Tohoku J Exp Med. 1987 Nov;153(3):197-205. [3433275 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Klotho

General Function:: Vitamin d binding
Specific Function:: May have weak glycosidase activity towards glucuronylated steroids. However, it lacks essential active site Glu residues at positions 239 and 872, suggesting it may be inactive as a glycosidase in vivo. May be involved in the regulation of calcium and phosphorus homeostasis by inhibiting the synthesis of active vitamin D (By similarity). Essential factor for the specific interaction between FGF23 and FGFR1 (By similarity).The Klotho peptide generated by cleavage of the membrane-bound isoform may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signaling.
Gene Name:: KL
Uniprot ID:: Q9UEF7
Molecular Weight:: 116179.815 Da

References

Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]

Target Details

2. NADPH oxidase 4

General Function:: Superoxide-generating nadph oxidase activity
Specific Function:: Constitutive NADPH oxidase which generates superoxide intracellularly upon formation of a complex with CYBA/p22phox. Regulates signaling cascades probably through phosphatases inhibition. May function as an oxygen sensor regulating the KCNK3/TASK-1 potassium channel and HIF1A activity. May regulate insulin signaling cascade. May play a role in apoptosis, bone resorption and lipolysaccharide-mediated activation of NFKB. May produce superoxide in the nucleus and play a role in regulating gene expression upon cell stimulation. Isoform 3 is not functional. Isoform 5 and isoform 6 display reduced activity.Isoform 4: Involved in redox signaling in vascular cells. Constitutively and NADPH-dependently generates reactive oxygen species (ROS). Modulates the nuclear activation of ERK1/2 and the ELK1 transcription factor, and is capable of inducing nuclear DNA damage. Displays an increased activity relative to isoform 1.
Gene Name:: NOX4
Uniprot ID:: Q9NPH5
Molecular Weight:: 66930.995 Da

References

Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]

Target Details

3. Solute carrier family 22 member 8

General Function:: Sodium-independent organic anion transmembrane transporter activity
Specific Function:: Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).
Gene Name:: SLC22A8
Uniprot ID:: Q8TCC7
Molecular Weight:: 59855.585 Da

References

Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. [25041433 ]
Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. [22419041 ]

Guanidinosuccinic acid (T3D4174)

Structure for T3D4174: Guanidinosuccinic acid

Targets

References

References

References