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Functional genomics and SNP analysis of human genes encoding proline metabolic enzymes

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Abstract

Proline metabolism in mammals involves two other amino acids, glutamate and ornithine, and five enzymatic activities, Δ1-pyrroline-5-carboxylate (P5C) reductase (P5CR), proline oxidase, P5C dehydrogenase, P5C synthase and ornithine-δ-aminotransferase (OAT). With the exception of OAT, which catalyzes a reversible reaction, the other four enzymes are unidirectional, suggesting that proline metabolism is purpose-driven, tightly regulated, and compartmentalized. In addition, this tri-amino-acid system also links with three other pivotal metabolic systems, namely the TCA cycle, urea cycle, and pentose phosphate pathway. Abnormalities in proline metabolism are relevant in several diseases: six monogenic inborn errors involving metabolism and/or transport of proline and its immediate metabolites have been described. Recent advances in the Human Genome Project, in silico database mining techniques, and research in dissecting the molecular basis of proline metabolism prompted us to utilize functional genomic approaches to analyze human genes which encode proline metabolic enzymes in the context of gene structure, regulation of gene expression, mRNA variants, protein isoforms, and single nucleotide polymorphisms.

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Abbreviations

GRE:

Glucocorticoid responsive element

OAT:

Ornithine-d-aminotransferase

OH-POX:

Hydroxyproline oxidase

OMIM:

Online Mendelian inheritance in man

P5C:

Δ1-Pyrroline-5-carboxylate

P5CDH:

P5C dehydrogenase

P5CS:

P5C synthase

P5CR:

P5C reductase

POX:

Proline oxidase

PRODH:

Proline dehydrogenase

SNP:

Single nucleotide polymorphism

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Acknowledgments

We thank Dr. K. Polyak, Harvard Medical School, for the RNA membrane that was blotted with total RNA isolated from DLD-1 cells infected with AD-p53. We also thank Mr. G. Steel and Ms. C. Obie, Johns Hopkins University School of Medicine, for their help and support. This work is supported by NM-INBRE grant (2 P20 RR016480-04), DOD PCRP (#W81XWH-05-1-0357), and NCI-RO1 (5RO1 CA106644) (to CAA. Hu), and by Howard Hughes medical Institute (to D. Valle).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA

    Chien-an A. Hu, D. Bart Williams, Siqin Zhaorigetu, Shadi Khalil & Guanghua Wan

  2. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    David Valle

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  1. Chien-an A. Hu
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  2. D. Bart Williams
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  3. Siqin Zhaorigetu
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  5. Guanghua Wan
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Correspondence to Chien-an A. Hu.

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Hu, Ca.A., Bart Williams, D., Zhaorigetu, S. et al. Functional genomics and SNP analysis of human genes encoding proline metabolic enzymes. Amino Acids 35, 655–664 (2008). https://doi.org/10.1007/s00726-008-0107-9

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  • DOI: https://doi.org/10.1007/s00726-008-0107-9

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