Perspectives, past, present and future: the proline cycle/proline-collagen regulatory axis

James M Phang

doi:10.1007/s00726-021-03103-7

Abstract

In the 35 years since the introduction of the “proline cycle”, its relevance to human tumors has been widely established. These connections are based on a variety of mechanisms discovered by many laboratories and have stimulated the search for small molecule inhibitors to treat cancer or metastases. In addition, the multi-layered connections of the proline cycle and the role of proline and hydroxyproline in collagen provide an important regulatory link between the extracellular matrix and metabolism.

Highlights

The first review of proline’s regulatory effects on cell metabolism appeared 35 years ago (Phang 1985), but accelerating discoveries during the last 10 years established the central role of proline in cancer biology
The linkage of proline metabolism is not limited to cancer but is evident in viral proliferation as seen in the hijacking of proline biosynthetic enzymes (PYCR1) by Kaposi’s sarcoma herpes virus K1 (Choi et al 2020) and MYC-dependent adenoviral proliferation (Thai et al 2015)
Recent studies by Dr Sarah Fendt in Leuven, Belgium showed that breast cancer cells grown as spheroids in 3-D cultures had a dependence on proline and Proline dehydrogenase (PRODH) for growth whereas they did not when grown in 2-D monolayers (Elia et al 2017)

Summary

Introduction

The first review of proline’s regulatory effects on cell metabolism appeared 35 years ago (Phang 1985), but accelerating discoveries during the last 10 years established the central role of proline in cancer biology. The recognition that P5C was the immediate degradative product of proline and its direct biosynthetic precursor, a relationship unique in intermediary metabolism, led to a model linking the two substrates in a metabolic cycle catalyzed by PRODH and PYCR (Phang et al 1980; Yeh et al 1984).

Results

Conclusion