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The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications

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Abstract

l-Glutamine is a nutritionally semi-essential amino acid for proper growth in most cells and tissues, and plays an important role in the determination and guarding of the normal metabolic processes of the cells. With the help of transport systems, extracellular l-glutamine crosses the plasma membrane and is converted into alpha-ketoglutarate (AKG) through two pathways, namely, the glutaminase (GLS) I and II pathway. Reversely, AKG can be converted into glutamine by glutamate dehydrogenase (GDH) and glutamine synthetase (GS), or be converted into CO2 via the tricarboxylic acid (TCA) cycle and provide energy for the cells. Different steps of glutamine metabolism (the glutamine-AKG axis) are regulated by several factors, rendering the glutamine-AKG axis a potential target to counteract cancer. Moreover, intracellular glutamine plays an important role in cellular homeostasis not only as a precursor for protein synthesis, but also for its nutritional roles in cell growth, lipid metabolism, insulin secretion, and so on. The main objective of this review is to highlight the metabolic pathways of glutamine to AKG, with special emphasis on nutritional and therapeutic use of glutamine-AKG axis to improve the health and well-being of animals and humans.

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Fig. 1

Adapted from (Pochini et al. 2014)

Fig. 2
Fig. 3

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Abbreviations

AKG:

Alpha-ketoglutarate

α-KGDH:

Alpha-ketoglutarate dehydrogenase

ADP:

Adenosine diphosphate

ASCT2:

ASC amino acid transporter-2

ATP:

Adenosine triphosphate

BCAT:

Branched-chain amino acid aminotransferase

BW:

Body weight

CREB2:

cAMP-responsive element binding 2

FOXO:

Forkhead box O

GDH:

Glutamate dehydrogenase

GLS:

Glutaminase

GPNA:

γ-l-Glutamyl-p-nitroanilide

GS:

Glutamine synthetase

GTP:

Guanosine triphosphate

GTPase:

Guanosine triphosphatase

HDL:

High density lipoproteins

HIF:

Hypoxia-inducible factor

IPEC-1:

Intestinal porcine epithelial cell-1

KGM:

Alpha-ketoglutaramate

KIC:

Alpha-ketoisocaproate

LAT1/2:

L-type amino acid transporter 1/2

LDL:

Low density lipids

MAPK:

Mitogen-activated protein kinase

MEFs:

Mouse embryonic fibroblasts

mTOR:

Mammalian target of rapamycin

mTORC1:

mTOR complex 1

NADH:

Nicotinamide adenine dinucleotide hydrogen

NADPH:

Reduced nicotinamide adenine dinucleotidephosphate

OKG:

Ornithine-ketoglutarate

PAG:

Phosphate-activated glutaminase

PI(3)K:

Phosphatidylinositol 3-kinase class I

PKB:

Protein kinase B

ROS:

Reactive oxygen species

S6K1:

p70 ribosomal protein S6 kinase

SIRT4:

Sirtuin 4

SNAT:

Sodium-coupled neutral amino acid transporter

TCA:

Tricarboxylic acid

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This study was jointly supported by the National Natural Science Foundation of China (31301985, 31472107, 31372326), the National Key Basic Research Program of China (2013CB127306), the China Postdoctoral Science Foundation (2014M562111, 2015T80871) and the Science and Technology Department of Hunan province (2015RS4035, 2015JC3126).

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    Authors and Affiliations

    1. College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, China

      Dingfu Xiao, Kang Yao & Yulong Yin

    2. Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients, Hunan Collaborative Innovation Center of Animal Production Safety, Changsha, 410128, Hunan, China

      Dingfu Xiao & Kang Yao

    3. Science College of Jiangxi Agricultural University, Nanchang, 330045, Jiangxi, China

      Liming Zeng

    4. Scientific Observation and Experiment Station of Animal Nutrition and Feed Science in South-Central China, Ministry of Agriculture, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, No. 644 Yuanda Road, Furong District, Changsha, 410125, Hunan, China

      Kang Yao, Xiangfeng Kong, Guoyao Wu & Yulong Yin

    5. Department of Animal Science, Texas A&M University, College Station, TX, 77843, USA

      Guoyao Wu

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    1. Dingfu Xiao
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    D. Xiao and L. Zeng contributed equally to this study.

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    Xiao, D., Zeng, L., Yao, K. et al. The glutamine-alpha-ketoglutarate (AKG) metabolism and its nutritional implications. Amino Acids 48, 2067–2080 (2016). https://doi.org/10.1007/s00726-016-2254-8

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