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    Topic review

    1-C Metabolism in AML

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    Submitted by: Kanwal Mahmood

    Definition

    One-carbon (1-C) metabolism is essential for numerous cancer cell functions, including protein and nucleic acid synthesis and maintaining cellular redox balance, and inhibition of the 1-C pathway has yielded several highly active drugs, such as methotrexate and 5-FU. 

    1. Introduction

    Acute Myeloid Leukemia (AML) is a heterogeneous hematologic neoplasm characterized by clonal evolution of hematopoietic stem/progenitor cells resulting in disruption of normal blood cell production and function. Despite the new approvals of therapeutic agents as well as allogeneic stem cell transplantation, the five-year survival rate for patients with AML remains less than 40% [1], underscoring the need for novel therapeutic strategies such as targeting metabolic pathways in AML that have recently become better understood.

    2. Metabolic Dysfunction in AML

    Metabolic alteration, in which malignant cells can alter metabolism by pushing the cell towards more glycolysis/glutaminolysis and dysfunctional oxidative phosphorylation, is now considered a hallmark of cancer [2][3]. Studies in AML have shown alterations in glucose (Warburg effect), fatty acid, folate, and amino acid metabolism pathways [2][4]. Due to metabolic reprogramming, neoplastic cells are able to proliferate and grow, and these metabolic liabilities can be exploited for the treatment of AML. Folate metabolism supports a set of biochemical reactions known as one-carbon (1-C) metabolism, which is a universal metabolic process that serves to produce and transfer 1-C units for biosynthetic processes in the cell including nucleic acid synthesis [5]. 1-C metabolism has been shown to be frequently altered in hematologic and solid neoplasms [4]. Anti-folates have been among the first efficacious anticancer agents and still hold a significant role in the treatment of many hematologic and solid malignancies.

    3. De Novo Serine/Glycine Biosynthesis

    3.1. Serine

    Serine is an amino acid that is synthesized through the de novo serine biosynthesis pathway and provides precursors to produce purines, pyrimidines, lipids, and antioxidants [6][7]. Serine biosynthesis begins with the conversion of glycolysis intermediate 3-phosphoglycerate (3-PG) to 3-phosphohydroxypyruvate (3-PHP) by the phosphoglycerate dehydrogenase (PHGDH) enzyme. Conversion of glutamate to α-ketoglutarate mediated by phosphoserine aminotransferase (PSAT1) results in the amination of 3-PHP producing 3-phosphoserine (3-PS). The final step involves the hydrolyzation of 3-PS to serine by phosphoserine phosphatase (PSP). The three enzymes involved in the serine biosynthesis pathway are reported to be upregulated in different neoplastic cells [8][9][10]. Specifically, it was demonstrated that silencing PHGDH has a detrimental effect on leukemia cell growth and survival [11][12] and PHGDH gene overexpression was among the 4-gene signature reported to be an independent negative prognostic marker in patients with AML [10].

    3.2. Glycine

    Glycine synthesis is an important reaction in which serine is used as a substrate. Serine hydroxymethyltransferases (SHMT), cytosolic (SHMT1), and mitochondrial (SHMT2), are responsible for the conversion of serine to glycine [13]. Glycine is one of the major sources of carbon donation for nucleotide biosynthesis involving the folic acid cycle [4][14][15]. The dependency of neoplastic cells on serine/glycine has been reported and can be further exploited pharmacologically [4][6]. For example, as a proof of concept, a dramatic decrease in colon cancer growth was reported following dietary restriction of serine and glycine [8][14]; a strategy that may also be applied to various hematologic neoplasms.

    Additionally, serine and glycine are heavily involved in the maintenance of cellular oxidative homeostasis [7][16]. Glutathione (GSH) is a tripeptide that consists of the amino acids cysteine, glycine, and glutamate [16]. GSH is the most abundant metabolite in the cell and is an important antioxidant that prevents oxidative damage caused by reactive oxygen species (ROS) and maintains the appropriate ratio of Nicotinamide adenine dinucleotide phosphate oxidase/Nicotinamide adenine dinucleotide phosphate (NADPH/NADP) [4][16]. Downregulation of any key enzymes in the serine biosynthesis pathway causes a decrease in GSH expression and a subsequent increase in ROS production [6][11].

    4. 1-C Metabolism

    4.1. Folate Cycle

    Folates are important for cellular metabolism, and outputs of the folate cycle include components that are essential for the synthesis of many macromolecules [8]. Recent studies have shown that in mammalian cells most of the 1-C units used in folate metabolism are derived from serine catabolism in mitochondria, [17] allowing the conversion of tetrahydrofolate (THF) to 5,10-methylenetetrahydrofolate (CH2-THF) by SHMT2. Folic acid can also be enzymatically reduced to dihydrofolate (DHF) and then further catalyzed by dihydrofolate reductase (DHFR) to produce THF [4]. CH2-THF is reduced to 5-methyl THF (CH3-THF) by the enzyme CH2-THF reductase (MTHFR) [4][6]. The concluding step of the folate cycle is the demethylation of the CH3-THF complex, back to THF through the transfer of the methyl group to vitamin B12 [18]. This final step of the folate pathway is linked to the start of the methionine pathway, as the methyl group bound to vitamin B12 and methionine synthase (MS) is transferred to homocysteine, converting it to methionine [18]. Since the folate cycle is coupled with the methionine cycle, it is therefore essential for producing methionine and homocysteine.

    CH2-THF dehydrogenase 2 (MTHFD2), an NAD+-dependent enzyme that is indirectly involved in 1-C metabolism, has been shown to be the most differentially expressed metabolic enzyme in cancer compared with normal cells [19]. Pikman et al. [20] reported that the suppression of MTHFD2 by shRNA impaired growth and promoted differentiation in AML cell lines. Furthermore, they showed that MTHFD2 suppression decreased leukemia burden and prolonged survival in MLL-AF9 mouse leukemia models and a human xenograft model [20].

    Polymorphisms in the gene coding region for DHFR have been implicated in chemoresistance to the anti-metabolite methotrexate in acute lymphoblastic leukemia (ALL) [4][21]. Studies by Dulucq et al. [22] showed that a single nucleotide polymorphism (SNP) in the promoter region of DHFR at A317G results in higher transcriptional activity of this enzyme, thereby conferring resistance to methotrexate treatment. These findings underscore the need for novel therapeutics that can bypass polymorphism-associated chemoresistance.

    4.2. Methionine Cycle

    The methionine cycle is the second half of the 1-C metabolism pathway. It is directly involved in the production of GSH, methylation of proteins, methylation of nucleic acids and subsequent epigenetic modulation, as well as the production of universal methyl group donor S-adenosylmethionine (SAM) [4]. The cycle begins with the demethylation of CH3-THF and conversion of homocysteine to methionine, which is subsequently converted to SAM by methionine adenosyltransferase (MAT). SAM is demethylated to produce S-adenosylhomocysteine (SAH), which is deadenylated to form homocysteine, completing a full turn of the methionine cycle [23]. Reduction of homocysteine to cysteine along with covalent bindings to glycine and glutamate produces GSH [4][5][6].

    In a study by Barve et al. [24] deprivation of exogenous methionine disrupted methionine and SAM metabolism, resulted in significant apoptosis and global changes in cellular methylation in AML cells. Furthermore, pharmacologic inhibition of SAH by deazaadenosine resulted in a drastic prolongation of overall survival of MLL-R Xenograft mouse model of AML.

    Genetic polymorphisms in the 1-C pathway have been studied extensively and are associated with numerous conditions, including cancer. The most well-studied polymorphism is the c.677C>T in the coding region of the MTHFR gene [25]. This non-synonymous polymorphism encodes a valine to alanine substitution on residue 222 [26], resulting in overexpression of both folate and homocysteine. Recent studies have shown that elevated homocysteine levels are a risk factor for diseases such as Alzheimer’s and cancer [27], highlighting the significance of polymorphisms as a variable in combination treatment.

    5. Glutamine Metabolism

    Hematologic and solid malignancies have both demonstrated a crucial dependence on glutamine for survival and proliferation; hence, interfering with glutamine metabolism and its plasma supply have emerged as promising clinically relevant therapeutic approaches for cancer [11][31][32]. Neoplastic cells frequently upregulate glutamine transporters[28] in response to their increased demand for energy, nucleic acid synthesis, and need to balance cellular oxidative state[1][28]. Conversion of glutamine to glutamate and ammonia by the glutaminase enzymes is the first step of glutaminolysis, which then feeds the mitochondrial Krebs cycle – even in the limited supply of glucose[29]—to provide energy to rapidly dividing neoplastic cells. 

    6. Conclusion

    While targeting serine/glycine/methionine has shown to be promising in the pre-clinical models of AML, these metabolic vulnerabilities should be combined with other clinically relevant amino acid-focused strategies to be translated efficiently and in a timely manner for prime-time clinical use. We propose that interference with glutamine metabolism is one of such promising strategies that is already utilized at the patient’s bedside for treatment of leukemias, lymphomas, and some solid tumors [30][31][32][33].

    This entry is adapted from 10.3390/ph14030190

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