Disease variants of human Δ1-pyrroline-5-carboxylate reductase 2 (PYCR2)

Patel, Sagar M.; Seravalli, Javier; Tanner, John J.; Becker, Donald F.

doi:10.1016/j.abb.2021.108852

Cited by 10 publications

(6 citation statements)

References 46 publications

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“…The variants in the NAD(P)‐binding domain have been reported in the other patients with HLD10 (Table S4). In addition, a recent study has validated the pathogenicity of the Arg119Cys variant, also in the NAD(P)‐binding domain, and showed that the Arg119Cys impairs catalytic efficiency of PYCR2 up to 366 times lower than that of the wild‐type enzyme, confirming its pathologic role in HLD10 (Patel et al, 2021). The above evidences suggest that the variants in the NAD(P)‐binding domain could interfere the PYCR2 function, leading to HLD10 phenotype.…”

Section: Discussionmentioning

confidence: 90%

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Manaspon

Boonsimma

Phokaew

et al. 2021

American J of Med Genetics Pt A

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PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three outof four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay.Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients.

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Section: Discussionmentioning

confidence: 90%

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Manaspon

Boonsimma

Phokaew

et al. 2021

American J of Med Genetics Pt A

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“…The culture was placed in a 37 °C shaker for approximately 6 h until the optical density at 600 nm (OD 600 ) was 0.8, at which point protein expression was induced by adding 0.2 mM IPTG to the culture for overnight induction at 18 °C. After overnight induction, the cells were incubated with 100 μg mL –1 chloramphenicol for 3 h at 18 °C as previously described . The cells were then harvested by centrifugation at 5000 rpm for 20 min at 4 °C and stored at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

“…After overnight induction, the cells were incubated with 100 μg mL –1 chloramphenicol for 3 h at 18 °C as previously described. 40 The cells were then harvested by centrifugation at 5000 rpm for 20 min at 4 °C and stored at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

“…DL-P5C used was synthesized as described previously 40 according to the protocol by Williams et al 41 and was freshly neutralized with 6 M NaOH to pH 7 immediately prior to the assays. In assays with DL-P5C as the variable substrate, NAD(P)H concentration was held fixed at 500 μM, whereas in assays with NAD(P)H as the variable substrate, DL-P5C concentration was kept fixed at 5 mM.…”

Section: Methodsmentioning

confidence: 99%

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Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

et al. 2023

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Pyrroline-5-carboxylate reductase (PYCR) is a proline biosynthetic enzyme that catalyzes the NAD(P)H-dependent reduction of Δ 1 -pyrroline-5-carboxylate (P5C) to proline. Humans have three PYCR isoforms, with PYCR1 often upregulated in different types of cancers. Here, we studied the biochemical and structural properties of the Thr171Met variant of PYCR1, which is found in patients with malignant melanoma and lung adenocarcinoma. Although PYCR1 is strongly associated with cancer progression, characterization of a PYCR1 variant in cancer patients has not yet been reported. Thr171 is conserved in all three PYCR isozymes and is located near the P5C substrate binding site. We found that the amino acid replacement does not affect thermostability but has a profound effect on PYCR1 catalytic activity. The k cat of the PYCR1 variant T171M is 100-to 200-fold lower than wild-type PYCR1 when P5C is the variable substrate, and 10-to 25-fold lower when NAD(P)H is varied. A 1.84 Å resolution X-ray crystal structure of T171M reveals that the Met side chain invades the P5C substrate binding site, suggesting that the catalytic defect is due to steric clash preventing P5C from achieving the optimal pose for hydride transfer from NAD(P)H. These results suggest that any impact on PYCR1 function associated with T171M in cancer does not derive from increased catalytic activity.

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“…Human PYCR1 X-ray crystal structures have been reported (Meng et al 2006a, b;Christensen 2017;Christensen et al 2020). A 1.85 Å structure of the ternary complex of PYCR1 with NADPH provides insights into the active site and NADPH binding in the Rao-Rossmann dinucleotide binding domain (Patel et al 2021). Taken together, PYCR1 could be a potential target for anticancer therapeutics and the results generated from the structure analysis and prediction, and in vivo studies are critical for this purpose.…”

Section: Human Pycrs and Associated Diseasesmentioning

confidence: 99%

Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer

2021

Amino Acids

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Δ 1 -Pyrroline-5-carboxylate (P5C) reductase (PYCR or P5CR) catalyzes the conversion of P5C to L-proline (Pro) with concomitant oxidation of a cofactor, NADPH or NADH. Mammalian PYCR have been studied since 1950' and currently three isozymes of human PYCR, 1, 2, and L, have been identified and characterized and their roles in genetic diseases and cancer biology have been keenly investigated. These three isozymes are encoded by three different genes localized at three different chromosomes, and catalyze NAD(P)H-dependent reduction of P5C to Pro important for the transfer of oxidizing potential across the mitochondrion and cell. The review summarizes the current understanding of these three human PYCR isozymes and their roles in diseases with a focus on cancer.

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Disease variants of human Δ1-pyrroline-5-carboxylate reductase 2 (PYCR2)

Cited by 10 publications

References 46 publications

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1

Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer

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Disease variants of human Δ1-pyrroline-5-carboxylate reductase 2 (PYCR2)

Cited by 10 publications

References 46 publications

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10

Functional Impact of a Cancer-Related Variant in Human Δ1-Pyrroline-5-Carboxylate Reductase 1

Isozymes of P5C reductase (PYCR) in human diseases: focus on cancer

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Functional Impact of a Cancer-Related Variant in Human Δ¹-Pyrroline-5-Carboxylate Reductase 1