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Chapter 7 Signaling Transduction and Metabolomics 73

Lactate Glucose
Amino
acids Fatty Acids
Plasma
membrance
Glucose
Pentose
Protein Fatty Acyl-CoA Glycogen Phosphate
Breakdown Pathway
LDHA
Lactate Pyruvate
ATP Amino
Mitochondrion acids NAD + NADH H +
+
PDK PDH
Respiratory
β-Oxidation
Chain of Fatty Acids
NAD + Acetyl-CoA
Nucleotides
+
NADH H + TCA
Cycle
GSH-mediated
CPT-1 NADPH
Palmitoyl-CoA Citrate ROS defense

Acetyl-CoA Cholesterol DNA, RNA
Synthesis
ACC
Malonyl-CoA
Triglyceride
Droplets FAS
Acyl-CoA Lipid Synthesis
Fig. 7.3 INTEGRATION OF CENTRAL METABOLIC PATHWAYS. The metabolic fluxes within anabolic
and catabolic routes are controlled by different signals including metabolite concentrations. These metabolic
pathways are localized in different cellular compartments to adequately provide cellular energetic and nutrient
homeostasis necessary for growth and survival. See text for further details. ACC, Acetyl-CoA carboxylase; CoA,
coenzyme A; FAS, fatty acid synthase; LDHA, lactate dehydrogenase A; PDH, pyruvate dehydrogenase; PDK,
pyruvate dehydrogenase kinase; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Chemokine Signaling STING signals to IKK to phosphorylate and degrade IκBα, which
sequesters NFκB in the cytoplasm. Both phosphorylated and dimer-
Chemokines mediate cell migration in immune surveillance, inflam- ized IRF3 and NFκB translocate to the nucleus to activate expression
mation, and development. There are nearly 50 human chemokines of type I interferons and other cytokines.
divided into four families (CXC, CC, C, and CX3C) on the basis of
the pattern of internal cysteine residues; thus C stands for cysteine
and X/X3, one or three noncysteine amino acids. Expression of METABOLOMICS AND CONTROL OF HEMATOPOIETIC
some of these chemokines is induced by inflammatory signals such CELL METABOLISM
as TNFα, interferon-γ, trauma, or microbial infection. There are
approximately 20 signaling chemokine receptors and they are all There are three important general pathways by which metabolism
GPCR receptors, thus the chemokine acts as a ligand, and activation impacts cellular function and the metabolomic state (Fig. 7.3):
of the chemokine receptor follows the principles described previously. (1) activity of catabolic routes that supply energy in the form of
The major downstream effectors are cAMP and calcium messengers. ATP, such as glycolysis or oxidative phosphorylation; (2) activity of
Interestingly, some of the chemokine receptors also bind HIV viral anabolic routes that synthesize molecules that are used for cellular
proteins. growth or a specific function; and (3) changes in metabolites that
control intrinsic and extrinsic cellular activities. This regulation
is intimately connected to signaling transduction, as most of the
cGAS–cGAMP–STING Signaling Pathway pathways described in the previous section directly control cellular
metabolism and metabolite levels. Here, this part of the review will
The presence of cytoplasmic DNA, through infection or DNA cover the main metabolic pathways and new metabolomic research,
damage, activates innate immune responses. A mechanism of taking into consideration their implications in hematopoietic cells.
sensing this misplaced DNA is through the cGAS–cGAMP–STING
signaling pathway. Cytosolic DNA binds and activates the cGAS
enzyme (cGAMP synthase), which produces a second messenger, the Glucose Metabolism
cyclic dinucleotide 2′,3′-cGAMP, using ATP and GDP as substrates.
2′,3′-cGAMP is a high-affinity ligand for STING, an endoplasmic Hematopoietic cells have different types of glucose transporters;
reticulum membrane protein that undergoes several structural con- for example, activation of T cells causes dramatic increases in
formations. 2′,3′-cGAMP bound to STING binds to the protein Glut1 expression in order to maintain immune homeostasis. Once
kinase TBK1, which phosphorylates IRF3; in addition, activated transported into the cell, glucose is metabolized through different