PHGDH: a novel therapeutic target in cancer

Abstract

Serine is a key contributor to the generation of one-carbon units for DNA synthesis during cellular proliferation. In addition, it plays a crucial role in the production of antioxidants that prevent abnormal proliferation and stress in cancer cells. In recent studies, the relationship between cancer metabolism and the serine biosynthesis pathway has been highlighted. In this context, 3-phosphoglycerate dehydrogenase (PHGDH) is notable as a key enzyme that functions as the primary rate-limiting enzyme in the serine biosynthesis pathway, facilitating the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Elevated PHGDH activity in diverse cancer cells is mediated through genetic amplification, posttranslational modification, increased transcription, and allosteric regulation. Ultimately, these characteristics allow PHGDH to not only influence the growth and progression of cancer but also play an important role in metastasis and drug resistance. Consequently, PHGDH has emerged as a crucial focal point in cancer research. In this review, the structural aspects of PHGDH and its involvement in one-carbon metabolism are investigated, and PHGDH is proposed as a potential therapeutic target in diverse cancers. By elucidating how PHGDH expression promotes cancer growth, the goal of this review is to provide insight into innovative treatment strategies. This paper aims to reveal how PHGDH inhibitors can overcome resistance mechanisms, contributing to the development of effective cancer treatments.

Fig. 1. Isoforms of PHGDH in various organisms.

Type I is dominant in humans, rodents, fungi, plant, and bacteria, while Types II and III are primarily found in bacteria. All four types share common features, such as a substrate-binding domain, nucleotide-binding domain, and amino and carboxyl termini. Notably, Type I PHGDH proteins possess an additional ASB domain and ACT domain, while Type II PHGDH proteins contain an ASB domain. Type III PHGDH proteins can be subdivided into two forms, which are determined by the presence of a histidine (type H) or a lysine (type K) in the active site. Allosteric substrate-binding (ASB); Aspartate kinase-chorismate mutase–tyrosinase A prephenate dehydrogenase (ACT).

Fig. 2. Posttranslational modifications of amino acid residues in PHGDH.

Lysine (K) 58, K146, K330, and arginine (R) 236 play a role in regulating the physiological functions of PHGDH. The structural image was sourced from the AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/).

Fig. 3. Overview of 1C metabolism.

PHGDH functions as the rate-limiting enzyme in serine synthesis, governing 1C metabolism. In 1C metabolism, PHGDH has the capacity to modulate the redox balance, nucleotide synthesis, and epigenetic processes. The folate cycle and the methionine cycle are the two primary cyclic processes in 1C metabolism. 3-phosphoglycerate (3PG); Tetrahydrofolate (THF); Methylenetetrahydrofolate reductase (MTHFR); Methionine adenosyltransferase 2 A (MAT2A); S-adenosyl methionine (SAM); S-adenosylhomocysteine (SAH); adenosylhomocysteinase (AHCY); Glutathione (GSH); Glutathione disulfide (GSSG); Serine hydroxymethyltransferase 1 (SHMT1); Serine hydroxymethyltransferase 2 (SHMT2); Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2); Methylene tetrahydrofolate 2-like (MTHFD2L).

Fig. 4. PHGDH is a novel anticancer therapeutic target for drug-resistant cancers.

PHGDH is crucial for combating cancer drug resistance. 5-Fluorouracil (5-FU); Chimeric antigen receptor-T cell (CAR-T cell).