Subsystem: Proline, 4-hydroxyproline uptake and utilization

This subsystem's description is:

The main route of Proline catabolism in bacteria and eukaryotes is via transformation to L-1-pyrroline-5-carboxylate (P5C, catalyzed by Proline dehydrogenase (EC, which in turn is oxidized to L-glutamate (catalyzed by Delta-1-pyrroline-5-carboxylate dehydrogenase (EC Both enzymatic activities reside in a bifunctional protein PutA in the majority of microorganisms. In addition to its enzymatic activities, the PutA protein acts as a repressor of putA and putP expression in response to proline supply in the majority of Gamma-Proteobacteria. DNA-binding activity resides in an additional ~50 aa N-terminal domain present in PutA in these organisms.

Alternative route of proline catabolism, in which Proline is converted to 5-aminovaleriate has been described in Clostridia. The process is catalyzed by a multi-subunit selenocysteine-containing Proline reductase (EC Proline racemese (located in the same cluster) ensures utilization of either L- or D-Pro.

Potentially Proline might also be utilized by pyrroline-5-carboxylate reductase (ProC, EC However, this enzyme preferentially acts in the biosynthesis of Pro (Kenklies et al. 1999), even though the reaction is reversible in some cases.

Proline transporters
Proline transporters are NOT encoded comprehensively in this SS. The ProP and ProY have been included tentatively; however, see Dr. Laszlo Csonka’s comments below:
(i) ProP can take up proline but for some reason (that could be very interesting), the proline that comes in through ProP cannot be used for catabolism by PrDH/P5CDH (PutA). ProP can take up proline as precursor for protein synthesis and as an osmoprotectant (along with glycine betaine), but not for use as a carbon or nitrogen source.
(ii) ProY was found by Stanley Maloy via a mutation that suppressed PutP mutations. However in the wild-type, it does not take up proline. I don't know whether the suppressor mutation was ever determined by sequencing, but it has been suggested that the mutation increases the expression of ProY. There is a very good chance that the real substrate for ProY is not proline and that it may be annotated as a proline transporter in other organisms only because of sequence similarity to the E. coli ProY.

4-hydroxyproline (4-Hyp).
The 4-hydroxyproline (4-Hyp) is present in large quantities in collagen and (to a lesser extend) in other animal proteins. It is present in all plants studied - from algae to angiosperms, in both - insoluble cell wall-bound proteins, and in soluble proteins, among them - in potato lectin, a soluble protein from Sandal, and other proteins present in cell sap or released into the medium of cultured cells. Most or all of the 4-Hyp residues in plant proteins are linked glycosidically through the Hyp hydroxyl to arabinose oligosaccharides, with one to four residues in furanosyl beta-linkage [1 -> 2 or 1 -> 3] (Koo and Adams, 1980). 4-Hyp is produced exclusively by post-translational hydroxylation of appropriate Pro residues, catalyzed by Peptidyl prolyl 4-hydroxylase (Pihlajaniemi et al., 1987; Helaakoski et al., 1994). Thus, 4-Hyp released by protein breakdown and subsequent hydrolysis of 4-Hyp-containing peptides cannot be directly reutilized for protein synthesis, and is committed to excretion or catabolism.

It is noteworthy, that even though 4-hydroxyproline apparently does not occur in structural components of bacterial cells (is present, however, in some antibiotics, e.g. etamycin, actinomycin), close homologs of Peptidyl prolyl 4-hydroxylase is detectable in a limited number of microbial species, including cyanobacteria, pathogenic Bacilli, Xantomonas, several marine organisms. Their function is enigmatic, their sporadic phylogenetic distribution points to potential horizontal transfer events (SG).

In animals the main route of 4-Hyp catabolism is catalyzed by the same enzymes as that of Proline (proline oxidase and hydroxyproline oxidase), yielding in case of 4-Hyp -- delta 1-pyrroline-3-hydroxy-5-carboxylate, converted further to 4-Hydroxy-2-oxoglutarate, and ultimately to glyoxylate and pyruvate.

A different route is under investigation in bacteria. This proposed inducible catabolic pathway for 4-Hyp proceeds via cis-4-hydroxy-D-proline and results in alpha-ketoglutarate semialdehyde (KGSA). A very interesting study of Ketoglutarate semialdehyde dehydrogenase, catalyzing the final step in this pathway (conversion of KGSA to alpha-ketoglutarate), present as multiple isozymes in many microbial species, has been published recently (Watanabe et al., 2007). Not all the genes required for this proposed pathway have been identified yet. One of them (potentially encoding 1-pyrroline-4-hydroxy-2-carboxylate deaminase (EC has been predicted in this Subsystem, based on it’s co-localization with known genes of the pathway. Two other hypothetical genes (abbreviated as Hyp2 and Hyp3 in this SS) are likely to be associated with this pathway, based on functional coupling data (RossO).


Elijah Adams and Leonard Frank. 1980. Metabolism of proline and the hydroxyprolines. A review. Amt Rev. Biochem., 49:1005-61

Pihlajaniemi T, Helaakoski T, Tasanen K, Myllylä R, Huhtala ML, Koivu J, Kivirikko KI. 1987. Molecular cloning of the beta-subunit of human prolyl 4-hydroxylase. This subunit and protein disulphide isomerase are products of the same gene. EMBO J., 6(3):643-9.

Helaakoski T, Veijola J, et al. 1994. Structure and expression of the human gene for the alpha subunit of prolyl 4-hydroxylase. The two alternatively spliced types of mRNA correspond to two homologous exons the sequences of which are expressed in a variety of tissues. J Biol Chem., 269(45):27847-54.

Watanabe S., M.Yamada|, Ohtsu I., and Makino K. 2007. Alpha-Ketoglutaric Semialdehyde Dehydrogenase Isozymes Involved in Metabolic Pathways of D-Glucarate, D-Galactarate, and Hydroxy-L-proline. Molecular and Metabolic Convergent Evolution. J. Biol. Chem., 282(9):6685-6695

Surber MW, Maloy S. 1998. The PutA protein of Salmonella typhimurium catalyzes the two steps of proline degradation via a leaky channel. Arch Biochem Biophys, 354(2):281-7

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