Pyruvate

Pyruvate (2-oxopropanoate) is a key metabolic intermediate and central hub between glucose, L-lactate, L-alanine, and acetyl-CoA and TCA cycle. Pyruvate concentration in plasma is very low (∼60 μM) as compared to the concentrations of glucose (∼5 mM) and lactate (∼1 mM). Kidneys maintain pyruvate/lactate ratio in circulation by converting lactate into pyruvate. Pyruvate, lactate, and acetate are transported across plasma membranes via monocarboxylate transporters.

Glucose and L-alanine are the main sources of intracellular pyruvate. Pyruvate is the end product of glycolysis, where it is formed from phosphoenolpyruvate (PEP) in a reaction catalyzed by pyruvate kinase (PK). Pyruvate can also be formed from lactate (and vice versa) in a reaction catalysed by L-lactate dehydrogenase (LDH).

pyruvate to acetyl-CoA conversion by PDH

Oxidative decarboxylation of pyruvate to acetyl-CoA and CO2 is irreversible reaction, catalysed by pyruvate dehydrogenase (PDH) complex. Acetate (from acetyl-CoA) is then consumed in the tricarboxylic acid (TCA) cycle forming CO2, or used in synthesis of other molecules.

Pyruvate radiopharmaceuticals for PET

1-[11C]Pyruvate

1-[11C]Pyruvate has been synthesized for imaging brain and cancer metabolism (Ropchan & Barrio, 1984; Hara et al., 1985). 1-[11C]Pyruvate PET was used to visualize brain tumours (Tsukiyama et al., 1986), brain ischaemia and infarction (Hara et al., 1986), mitochondrial encephalomyopathy and Leigh's disease in the brain (Toyoda et al., 1989), and muscle (Yokoi et al., 1990).

The 1-[11C]pyruvate is assumed to be taken up in tissues rapidly, then used in mitochondria and released as [11C]CO2 rapidly, unless oxidative utilization of pyruvate is defective, in which case 1-[11C]pyruvate is converted into [11C]lactate, with slow clearance from tissue (Tsukiyama et al., 1986; Yokoi et al., 1990).

3-[11C]Pyruvate

3-[11C]Pyruvate has been synthesized to be used as precursor for other radiopharmaceuticals (Bjurling et al., 1988). Its use for PET imaging was studied in minipig model before, during, and after induction of non-insulin dependent diabetes with alloxan (Hartvig et al., 1989). Initial myocardial uptake of 3-[11C]pyruvate and 1-[11C]palmitate was similar. The elimination of 3-[11C]pyruvate was slower in diabetic than healthy heart (Hartvig et al., 1989).

[18F]Fluoropyruvate

[18F]-3-fluoropyruvate has been synthesized to study whether it could be used for imaging metabolism in vivo, because it is a known substrate for pyruvate carboxylase, LDH, and inhibitor of PDH complex, and it is considerably less toxic than fluoroacetate (Graham et al., 2014). [18F]-3-Fluoropyruvate has shown low cell uptake in vitro, low tissue uptake in mouse in vivo, except in bones due to defluorination, and high activity in bladder (Graham et al., 2014). Considering the biological activity of 3-bromopyruvate the minimal tissue uptake of [18F]-3-fluoropyruvate was unexpected, and possibly caused by the hydrated isoform that 3-fluoropyruvate forms in aqueous solutions (Graham et al., 2014).

Pyruvate kinase

In the last step of glycolysis, pyruvate is formed from phosphoenolpyruvate (PEP) in a reaction catalyzed by pyruvate kinase (PK). There are four isozymes of pyruvate kinase: PKL in liver, PKR in red blood cells, PKM1 in differentiated cells in tissues such as muscle and brain, and PKM2 in proliferating cells including cancer cells.

PKL and PKR are allosterically regulated, with the active from stabilized by PEP and fructose 1,6-biphosphate, and the inactive state stabilized by ATP and L-alanine. PKM1 and PKM2 can form tetramers which are highly active; PKM1 is stable in its tetrameric form, while PKM2 is highly regulated by switching it between tetrameric and inactive dimeric forms. By high expression of PKM2, cancer cells can rapidly switch between anabolic and catabolic metabolism, with inhibited PKM2 promoting synthesis of macromolecules from glycolytic intermediates and activated PKM2 favouring energy production. Therefore PKM2 is an interesting target for cancer imaging, especially in the brain which normally expresses PKM1 (Witney et al., 2016; Beinat et al., 2021).

Activation of PKM2, for example by using N,N-diarylsulfonamide (DASA) compound DASA-23, inhibits tumour growth (Boxer et al., 2010; Anastasiou et al., 2012). DASA-23 has high potency as PKM2 activator through reversible binding and selective for PKM2 compared to other PK isozymes (Boxer et al., 2010). [11C]DASA-23 is rapidly and specifically taken up by tumour cells in vitro according to their PKM2 expression (Witney et al., 2016; Beinat et al., 2017). In vitro study with glioblastoma cell lines showed that [11C]DASA-23 could detect the glycolytic response to anti-neoplastic drugs (Beinat et al., 2020a). In vivo uptake in prostate cancer xenografts in mice was modest (Beinat et al., 2018), but better in glioblastoma xenografts (Beinat et al., 2021). In humans, [11C]DASA-23 can passively pass blood-brain barrier, and is cleared from the body by both hepatobiliary and urinary excretion (Beinat et al., 2020b). In patients with glioma, [11C]DASA-23 PET could outline tumours and show early metabolic non-response to treatment (Beinat et al., 2021).


See also:


Literature

Beinat C, Patel CB, Haywood T, Shen B, Naya L, Gandhi H, Holley D, Khalighi M, Iagaru A, Davidzon G, Gambhir SS. Human biodistribution and radiation dosimetry of [18F]DASA-23, a PET probe targeting pyruvate kinase M2. Eur J Nucl Med Mol Imaging 2020; 47(9): 2123-2130. doi: 10.1007/s00259-020-04687-0.

Bisswanger H. Fluoropyruvate: a potent inhibitor of the bacterial and the mammalian pyruvate dehydrogenase complex. Biochem Biophys Res Commun. 1980; 95(2): 513-519. doi: 10.1016/0006-291x(80)90814-1.

Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, Prasad PD. Sodium-coupled monocarboxylate transporters in normal tissues and in cancer. AAPS J. 2008; 10(1): 193-199. doi: 10.1208/s12248-008-9022-y.

Graham K, Müller A, Lehmann L, Koglin N, Dinkelborg L, Siebeneicher H. [18F]Fluoropyruvate: radiosynthesis and initial biological evaluation. J Labelled Comp Radiopharm. 2014; 57(3): 164-171. doi: 10.1002/jlcr.3183.

Halestrap AP. The SLC16 gene family - structure, role and regulation in health and disease. Mol Aspects Med. 2013; 34(2-3): 337-349. doi: 10.1016/j.mam.2012.05.003.

Magistretti PJ, Allaman I. A Cellular perspective on brain energy metabolism and functional imaging. Neuron 2015; 86: 883-901. doi: 10.1016/j.neuron.2015.03.035.

Tyson RL, Gallagher C, Sutherland GR. 13C-Labeled substrates and the cerebral metabolic compartmentalization of acetate and lactate. Brain Res. 2003; 992: 43-52. doi: 10.1016/j.brainres.2003.08.027.

van Heijster FHA, Heskamp S, Breukels V, Veltien A, Franssen GM, Jansen KCFJ, Boerman OC, Schalken JA, Scheenen TWJ, Heerschap A. Pyruvate-lactate exchange and glucose uptake in human prostate cancer cell models. A study in xenografts and suspensions by hyperpolarized [1-13C]pyruvate MRS and [18F]FDG-PET. NMR Biomed. 2020; 33(10): e4362. doi: 10.1002/nbm.4362.

Yokoi F, Hara T, Iio M, Nonaka I, Satoyoshi E. 1-[11C]pyruvate turnover in brain and muscle of patients with mitochondrial encephalomyopathy. A study with positron emission tomography (PET). J Neurol Sci. 1990; 99(2-3): 339-348. doi: 10.1016/0022-510x(90)90168-m.



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Updated at: 2023-03-08
Created at: 2023-01-25
Written by: Vesa Oikonen