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Birth of a pathway for sulfur metabolism in early amniote evolution

Nature Ecology & Evolution volume 4, pages 1239–1246 (2020)Cite this article

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Abstract

Among amniotes, reptiles and mammals are differently adapted to terrestrial life. It is generally appreciated that terrestrialization required adaptive changes of vertebrate metabolism, particularly in the mode of nitrogen excretion. However, the current paradigm is that metabolic adaptation to life on land did not involve synthesis of enzymatic pathways de novo, but rather repurposing of existing ones. Here, by comparing the inventory of pyridoxal 5'-phosphate-dependent enzymes in different amniotes, we identify in silico a pathway for sulfur metabolism present in chick embryos but not in mammals. Cysteine lyase contains haem and pyridoxal 5'-phosphate co-factors and converts cysteine and sulfite into cysteic acid and hydrogen sulfide, respectively. A specific cysteic acid decarboxylase produces taurine, while hydrogen sulfide is recycled into cysteine by cystathionine beta-synthase. This reaction sequence enables the formation of sulfonated amino acids during embryo development in the egg at no cost of reduced sulfur. The pathway originated around 300 million years ago in a proto-reptile by cystathionine beta-synthase duplication, cysteine lyase neofunctionalization and cysteic acid decarboxylase co-option. Our findings indicate that adaptation to terrestrial life involved innovations in metabolic pathways, and reveal the molecular mechanisms by which such innovations arose in amniote evolution.

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Fig. 1: Identification of genes involved in sulfonated amino acid biosynthesis in G. gallus.
Fig. 2: CL, CBS and CSAD genes are expressed from the early stages of embryogenesis.
Fig. 3: The CL pathway for taurine biosynthesis.
Fig. 4: Origin and conservation of the CL pathway in birds and reptiles.

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Data availability

Data and supplementary information are available in the manuscript. Raw data, sequence alignments and trees for Figs. 1–4 and Extended Data figures are deposited in the Harvard dataverse repository (https://doi.org/10.7910/DVN/UYAUBO). PLPomes of the amniotes analysed in this study and other organisms can be accessed and compared with the B6 database (http://bioinformatics.unipr.it/B6db).

Code availability

The R script containing the equation and commands (SM.tar.gz) used to produce the fitting shown in Fig. 1j is provided in the dataset deposited at the Harvard dataverse repository (https://doi.org/10.7910/DVN/UYAUBO).

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Acknowledgements

We thank D. E. Brodersen, D. Cavazzini, R. Tirindelli and A. Totaro for help and discussions. This work was supported by the Italian Ministry for Education, University and Research (MIUR) PRIN 2017 (grant no. 2017483NH8_003, to R.P.) and benefited from the equipment and framework of the COMP-HUB initiative, supported by the MIUR ‘Departments of Excellence’ programme no. 2018-2022, and from the High Performance Computing facility of the University of Parma, Italy. Chicken in situ hybridization studies were supported by NIH grant no. P41HD088362, to P.B.A.

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Authors and Affiliations

  1. Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy

    Marco Malatesta, Giulia Mori, Alessio Peracchi & Riccardo Percudani

  2. Centro Interdipartimentale Misure ‘Giuseppe Casnati’, University of Parma, Parma, Italy

    Domenico Acquotti

  3. Department of Food and Drug, University of Parma, Parma, Italy

    Barbara Campanini

  4. Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA

    Parker B. Antin

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Contributions

R.P. and M.M. performed bioinformatics. M.M. performed protein production. M.M. and G.M. performed protein characterization. P.B.A. supervised in situ hybridization. D.A. supervised NMR spectroscopy. B.C. supervised fluorescence spectroscopy. A.P. conceived and curated B6db. R.P. conceived the study and wrote the manuscript, with contributions by P.B.A., G.M., M.M., B.C. and A.P.

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Correspondence to Riccardo Percudani.

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Extended data

Extended Data Fig. 1 In silico subtraction of chicken and human PLPomes.

Comparison of the complete set of PLP-dependent enzymes (one isoform per gene) in Gallus gallus and Homo sapiens as classified by B6db. Orthologous proteins (BRH test) are colored blue. Gallus proteins without human orthologs are in bold. E-values indicate significance of the protein alignments with family-level Hidden Markov Models.

Extended Data Fig. 2 GgCL is a heme and PLP protein with cysteine lyase activity.

a, Multiple alignment of H. sapiens CBS (HsCBS) with G. gallus CBS and CL proteins (GgCBS, GgCL). Filled circles indicate residues that recognize heme (red), PLP (yellow) and serine (white) in the holo CBS structure (PDB code 3PC4). Conserved residues based on the alignment of 8 CL and 22 CBS sequences from vertebrates are shaded in black. Green shading indicates conserved differences between CBS and CL groups. b, Photograph of the FPLC collector after cation exchange, showing the vivid orange color of GgCL protein fractions (upper panel); selected fractions were subjected to SDS-PAGE electrophoresis and stained with Coomassie Brilliant Blue (lower panel). c, Gel filtration chromatogram (Superdex 200) with dual wavelength detection (λ = 280, 428 nm), showing a molecular weight corresponding to GgCL monomer. d, GgCL predicted interactions with heme (left) and PLP (right) are shown with residues conserved in the alignment of CBS/CL proteins highlighted in colors. e, Absorbance spectrum of recombinant GgCL (16.5 µM) in NaH2PO4 (20 mM), pH 7.0. f, Fluorescence emission spectrum (excitation: 412 nm) of recombinant GgCL (22 µM) in NaH2PO4, pH 7.0. g, Kinetics of H2S release by the CL reaction monitored spectrophotometrically at 390 nm in 50 mM NaH2PO4, pH 7.0 with GgCL (1 μM), lead acetate (0.4 mM), cysteine (5 mM) in the absence (dashed line) or in the presence of Na2SO3 (5 mM, solid line). h-i, Non linear fitting to the Michaelis Menten equation of the dependency on substrate concentrations of the initial reaction velocity of GgCL (1 μM) with fixed (h) Na2SO3 (5 mM) and (i) cysteine (40 mM). Data are means ± SDV of three independent experiments. j, Time-resolved 1H NMR spectra of cysteine (10 mM) in the presence of GgCL (1 µM), showing partial conversion into lanthionine.

Extended Data Fig. 3 Absence of CBS activity in GgCL.

a, Time-resolved 1H NMR spectra of 5 mM of serine (atoms labeled in blue) and 5 mM of DL-homocysteine (atoms labeled in red) in the presence of GgCL (1 µM). b, Time-resolved 1H NMR spectra of serine (5 mM) and Na2S (5 mM) in the presence of GgCL (1 µM). c, Time-resolved 1H NMR spectra of 5 mM of serine (atoms labeled in blue) and 10 mM of DL-homocysteine (atoms labeled in red) in the presence of GgCBS (4 µM), showing complete consumption of serine and partial conversion of DL-homocysteine in cystathionine (atoms labeled in green) due to the stereospecific enzymatic reaction. d, Hydrogen-Deuterium exchange of serine alpha proton catalysed by GgCL (1 µM) in 95% D2O. Spectra were superimposed at time 0’ (red), 60’ (green), 260’ (black). e, 1H peak integration of serine C𝛼 proton is plotted in the interval 0’−260’.

Extended Data Fig. 4 Gallus CSAD encodes a PLP-dependent cysteic acid decarboxylase (CAD).

a, Absorbance spectrum of GgCAD in 20 mM NaH2PO4, pH 8.0 and 100 mM NaCl; The absorbance region of PLP tautomers (enolimine 340 nm, ketoenamine 415 nm) is shown in the inset. b, Fluorescence emission spectrum of PLP enolimine tautomer upon excitation at 340 nm. c, Time-resolved 1H NMR spectra of cysteine sulfinic acid (5 mM) in the presence of GgCAD (1 µM), showing partial formation of hypotaurine (inset). d, Time-resolved 1H NMR spectra of 5 mM of cysteic acid (atoms labeled in blue) and 5 mM of hypotaurine (atoms labeled in red) in the presence of GgCAD (1 µM), showing slight inhibition of CAD activity. e, Time-resolved 1H NMR spectra of 5 mM of cysteic acid (atoms labeled in blue) and 5 mM of cysteine sulfinic acid (atoms labeled in red) in the presence of GgCAD (1 µM), showing strong inhibition of CAD activity. f, 1H peak integration of CA signals in the presence of GgCAD and hypotaurine (CA+Hyp) or cysteine sulfinic acid (CA+CSA).

Extended Data Fig. 5 Analysis of Gallus CSAD site-directed mutants.

a, Multiple alignment of CSAD orthologs from (1) non-sauropsids and (2) sauropsids. Conserved differences between groups are shaded in green. Residues that recognize PLP (yellow) or line the active site cavity (white) or are within 5 Å from the active site cavity (blue) in the human holo CSAD structure (PDB code 2JIS) are indicated by filled circles; positions of site-directed mutants are indicated by red arrows. b, Specific activities of wild-type (WT), single (Q467V, T470A), and double (Q467V/T470A) GgCAD mutants with CA and CSA substrates. c, 1H NMR spectra showing decarboxylation activity of wild-type (WT), single (Q467V, T470A) and double (Q467V-T470A) mutants in the presence of cysteic acid (right) and cysteine sulfinic acid (left) after 5’ of reaction stopped with 1 M HCl.

Extended Data Fig. 6 One-pot enzymatic synthesis of taurine from cysteine.

a, Time-resolved 1H NMR spectra of cysteine (5 mM) and sulfite (7 mM) in the presence of recombinant GgCL (1 µM) and GgCAD (1 µM) proteins. b-d, 1H peak integration of (b) cysteine, (c) taurine, and (d) serine NMR signals in the same reaction conditions as (a) in the absence (black dots) or in the presence (blue dots) of serine (5 mM) and GgCBS (4 µM).

Extended Data Fig. 7 Phylogeny of CBS and CL proteins in vertebrates.

Unrooted maximum-likelihood (ML) trees obtained from protein and nucleotide alignments of 35 CBS and CL sequences from 26 vertebrate species. Protein and nucleotide accession numbers corresponding to tree tip names are indicated; sauropsidian sequences are shaded in blue. Scale bars represent the number of calculated substitutions per site. a, Protein ML tree (436 alignment patterns) showing branching of the CL clade basal to teleostei. b, Nucleotide ML tree (1277 alignment patterns) showing branching of the CL clade basal to amniotes. c, Third codon position ML tree (613 alignment patterns) showing branching of the CL clade within sauropsida.

Extended Data Fig. 8 Ancestral substitutions in CL neofunctionalization.

a, Evolutionary dendrogram used in ancestral state reconstructions assuming split of amniote last common ancestor (Amniote; N2) into two lineages before the gene duplication (GD; N12) leading to saurospidian CL (sCL; N13) and CBS (sCBS; N21). Sequence identifiers are as in Supplementary Fig. 7. b, Multiple alignment of reconstructed ancestral sequences corresponding to nodes N2, N12, N13, and N21. Active site residues are indicated by blue triangles. Positions with Identical residues in the four nodes and human CBS are shaded gray. Numeration is in accordance with the human CBS sequence. c, Character state probabilities for active site residues substituted in GgCL showing high probability of fixation before the split of extant sauropsids.

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Malatesta, M., Mori, G., Acquotti, D. et al. Birth of a pathway for sulfur metabolism in early amniote evolution. Nat Ecol Evol 4, 1239–1246 (2020). https://doi.org/10.1038/s41559-020-1232-4

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