Food-derived peptides with inhibitory capacity for HMG-CoA reductase activity: a potential nutraceutical for hypercholesterolemia

Guillermo Santos-Sánchez; Ana Isabel Álvarez-López; Eduardo Ponce-España; Patricia Judith Lardone; Antonio Carrillo-Vico; Ivan Cruz-Chamorro

doi:10.26599/FSHW.2023.9250001

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Open Access

Food-derived peptides with inhibitory capacity for HMG-CoA reductase activity: a potential nutraceutical for hypercholesterolemia

Guillermo Santos-Sánchez^{^a^,^b}(), Ana Isabel Álvarez-López^{^a^,^b}, Eduardo Ponce-España^{^a^,^b}, Patricia Judith Lardone^{^a^,^b}, Antonio Carrillo-Vico^{^a^,^b}(), Ivan Cruz-Chamorro^{^a^,^b}

Instituto de Biomedicina de Sevilla, Instituto de Biomedicina de Sevilla (IbiS); Hospital Universitario Virgen del Rocío; Consejo Superior de Investigaciones Científicas (CSIC); Universidad de Sevilla, Seville 41013, Spain

Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Facultad de Medicina, Universidad de Sevilla, Seville 41009, Spain

Peer review under responsibility of Tsinghua University Press.

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Highlights

• Several food-derived peptides have been shown to inhibit the HMG-CoAR activity.

• Biopeptides inhibit HMG-CoAR activity by competitive or non-competitive mechanisms.

• Physicochemical characteristics of peptides define the type of enzyme inhibition.

• Food-derived peptides may help to reduce the side effects of statin therapy.

• Biopeptides are potential compounds as future hypocholesterolemic treatments.

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Abstract

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disease burden. Statins are the most prescribed lipid-lowering drugs to treat hypercholesterolemia and prevent CVDs. The biochemical mechanism of statins consists of competitive inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase enzyme (HMG-CoAR), the limiting enzyme in cholesterol biosynthesis. Due to statin intolerance in some patient groups, the search for new inhibitors is a field of great interest. This review focusses on the studies reporting the inhibitory effect of protein hydrolysates and biopeptides on the HMG-CoAR enzyme activity. The analysis of the action mechanism and physicochemical characteristics of the HMG-CoAR inhibitory peptides revealed that the molecular weight, amino acid composition, charge, and polarity are key aspects of the interaction with the HMG-CoAR enzyme. In conclusion, this review reveals the potential of using food peptides as new cholesterol-lowering agents and opens a new interesting field of research. However, clinical approaches are mandatory to confirm their therapeutic hypercholesterolemic effect.

Keywords

Functional foods Cholesterol Cardiovascular diseases Statins 3-Hydroxy-3-methylglutaryl-coenzyme A

References

[1]

World Health Organization, Cardiovascular diseases (CVDs), 2021. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).

[2]

N. Townsend, D. Kazakiewicz, F. Lucy Wright, et al., Epidemiology of cardiovascular disease in Europe, Nat. Rev. Cardiol. 19 (2021) 133-143. https://doi.org/10.1038/s41569-021-00607-3.

Source	Hydrolysate/peptides	Enzyme	Temperature (℃)	pH	Time	Reference
		in vitro experiments
		Legumes
Cowpea (Vigna unguiculata)	Hydrolysate GCTLN	Pepsin (P) + Pancreatin (Pa)	37	2 (P)7 (Pa)	2 h (P) + 2 h (Pa)	[43, 46]
	MPNY
	IAF
	QGF
	Pyr-GF	Pepsin (P) + Pancreatin (Pa)	37	2 (P)	3 h (P) + 3 h (Pa)	[44-45, 47]
	Pyr-GF	Pepsin (P) + Pancreatin (Pa)	37	7 (Pa)		[44-45, 47]
	QDF
	GCTLN
	GSTLN
Lupin	Hydrolysates	Pepsin	37	2	18 h	[50-51]
(Lupinus albus)	Hydrolysates	Trypsin	37	8	18 h	[50-51]
	LILPKHSDAD
	LPKHSDAD
	LTFPGSAED	Pepsin	37	2	18 h	[54-57]
	LTFPG
	YDFYPSSTKDQQS
	GQEQSHQDEGVIVR	Trypsin	37	2	18 h	[52]
Soy (Glycine max)	YVVNPDNDENYVVNPDNNEN	Pepsin (P) + Pancreatin (Pa)	37	2 (P)7.5 (Pa)	1 h (P) + 2 h (Pa)	[67]
	LPYPIAVPIAVPGEVAIAVPTGVA	Pepsin	25–60	1.5–3.5	2–24 h	[60-63, 65]
Pigeon pea (Cajanus cajan)	NALEPDNRIESEGGNALEPDNRIESPFVKSEPIPETNNE	Synthetic	-	-	-	[74]
Mung bean (Vigna radiata)	Hydrolysate	Pepsin (P) + pancreatin (Pa)	37	1 (P)8 (Pa)	0–6 h	[93]
		Seeds
		Pepsin	37	2	16 h
		Trypsin	37	7	16 h
Hempseed (Cannabis sativa)	Hydrolysates	Pancreatin	37	7	16 h	[78-79]
		Pepsin (P) + trypsin (T) + pancreatin (Pa)	37	2 (P)8.5 (T; Pa)	2 h (P) + 4 h (T + Pa)
Amaranth (Amaranthus cruentus)	HydrolysateGGVIVGVGVL	Multi-enzymes mix (trypsin + α-chymotrypsin + peptidase)	37	8	10 min	[82]
Chia (Salvia hispanica)	Hydrolysates	Alcalase	50	7	4 h	[35]
		Flavourzyme	50	8	4 h
		Alcalase (A) + Flavourzyme (F)	50 (A) + 50 (F)	7 (A)8 (F)	1 h (A) + 3 h (F)
		In vitro and in vivo experiments
		Legumes
Lupin (Lupinus angustifolius)	Hydrolysate	Alcalase	50	8	15 min	[29]
Chickpea (Cicer arietinum)	Hydrolysate VFVRN	Alcalase	50	7	4 h	[71]
		Others
Olive (Olea europaea)	Hydrolysate	Alcalase	50	8.5	4 h	[84]

Source	Hydrolysate/peptides	Enzyme/bacterium	Temperature (℃)	pH	Time	Reference
Note: n/a, not available.
Dry-cured ham	AA AL AQ DA DD EE ES LL QQ VH	α-Glucosidase	37	6.8	5 min	[85]
Fish (C. striata) skin	Hydrolysate	Collagenase (from B. licheniformis)	37	n/a	18 h	[87]
Bekasam (C. striata and Rasbora sp.)	Hydrolysate KGENYNTGVTPNLRPKAAEVVAFLNKE AIEAIADTMKK	Fermentation with L. acidophilus	25, 30, and 37	5.5, 7.0, and 8.5	5 days	[88]
Silkworm pupae (B. mori)	Hydrolysate HPP SGQR QPGP CQP NQR	Neutral proteinase	52	7	5 h	[89]
Goat milk	ITVDDKHYQK NMAIHPR TNAIPYVR TNAIPYVRYL	n/a	n/a	n/a	n/a	[90]

Competition	Source	Peptide sequence	PRS^a	Ho (kcal/mol)^b	Charge^b	Length	MW (Da)^b	Ring^c	N-terminal	C-terminal
Note: ^a PeptideRanker score (PRS) calculated according to http://distilldeep.ucd.ie/PeptideRanker/; ^b Calculated by the ToxinPred tool; ^c Calculated as the sum number of the amino acids H + F + P + Y + (W x 2). U-Mann Whitney test was applied to study the statistical differences between the mean of the chemical characteristics of peptides that inhibit HMG-CoAR by the L-domain or S-domain interaction. P-value ≤ 0.05 was considered statistically significant. S.D., standard deviation; ^†, hydrophobic amino acids;^§, negatively charged amino acids.
L-domain	V. unguiculata	IAF	0.820	0.53	0.00	3.00	349.46	1	I^†	F
		QGF	0.941	0.03	0.00	3.00	350.41	1	Q	F
		Pyr-GF	0.995	0.39	0.00	2.00	222.26	1	G^†	F
		QDF	0.741	−0.27	−1.00	3.00	408.44	1	Q	F
		MPNY	0.740	−0.11	0.00	4.00	523.65	2	M^†	Y
		LILPKHSDAD	0.117	−0.11	−0.50	10.00	1223.5	2	L^†	D^§
		LPKHSDAD	0.125	−0.28	−0.50	8.00	997.14	2	L^†	D^§
	L. albus	LTFPGSAED	0.135	−0.03	−2.00	9.00	1051.2	2	L^†	D^§
	L. albus	YDFYPSSTKDQQS	0.115	−0.33	−1.00	13.00	1565.78	4	Y^†	S
		GQEQSHQDEGVIVR	0.153	−0.29	−1.50	14.00	1738.08	1	G^†	R
		LPYP	0.818	0.1	0.00	4.00	488.63	3	L^†	P
		IAVPGEVA	0.102	0.22	−1.00	8.00	754.99	1	I^†	A
	G. max
		IAVPTGVA	0.124	0.28	0.00	8.00	726.98	1	I^†	A
	C. arietinum	VFVRN	0.226	−0.14	1.00	5.00	633.81	1	_V†	N
	Dry-cured ham	AA	0.191	0.25	0.00	2.00	160.18	0	A^†	A
		AL	0.438	0.39	0.00	2.00	202.27	0	A^†	L
		AQ	0.122	−0.22	0.00	2.00	217.24	0	A^†	Q
		DA	0.131	−0.23	−1.00	2.00	204.19	0	D	A
		DD	0.099	−0.72	−2.00	2.00	248.2	0	D	D^§
		EE	0.022	−0.62	−2.00	2.00	276.26	0	E	E^§
		ES	0.038	−0.44	−1.00	2.00	234.22	0	E	S
		LL	0.619	0.53	0.00	2.00	244.36	0	L^†	L
		QQ	0.082	−0.69	0.00	2.00	274.3	0	Q	Q
		VH	0.069	0.07	0.50	2.00	254.31	1	_V†	H
	B. mori	HPP	0.756	−0.18	0.50	3.00	349.42	3	H	P
		SGQR	0.369	−0.64	1.00	4.00	446.51	0	S	R
		QPGP	0.803	−0.17	0.00	4.00	397.48	2	Q	P
		CQP	0.707	−0.24	0.00	3.00	346.43	1	C	P
		NQR	0.167	−1.03	1.00	3.00	416.47	0	N	R
	Goat milk	NMAIHPR	0.462	−0.23	1.50	7.00	838.09	2	N	R
		TNAIPYVR	0.288	−0.14	1.00	8.00	933.18	2	T	R
		TNAIPYVRYL	0.412	−0.06	1.00	10.00	1209.55	3	T	L
		YVVNPDNDEN	0.070	−0.3	−3.00	10.00	1178.31	2	Y^†	N
		YVVNPDNNEN	0.075	−0.29	−2.00	10.00	1177.33	2	Y^†	N
	G. max
		IAVP	0.200	0.36	0.00	4.00	398.55	1	I^†	P
Mean ± S.D.			0.35 ± 0.31	−0.14 ± 0.37	−0.31 ± 1.04	5.14 ± 3.55	601.20 ± 426.50	1.20 ± 1.08	20/35	5/35
	V. unguiculata	GCTLN	0.402	−0.02	0.00	5.00	506.64	0	G^†	N
	V. unguiculata	GSTLN	0.196	−0.08	0.00	5.00	490.58	0	_G†	N
S-domain		YVVNPDNDEN	0.070	−0.3	−3.00	10.00	1178.31	2	Y^†	N
		YVVNPDNNEN	0.075	−0.29	−2.00	10.00	1177.33	2	_Y†	N
	G. max
		IAVP	0.200	0.36	0.00	4.00	398.55	1	I^†	P
		NALEPDNRIESEGG	0.176	−0.29	−3.00	14.00	1500.74	1	N	G
	C. cajan	NALEPDNRIES	0.129	−0.35	−2.00	11.00	1257.47	1	N	S
		PFVKSEPIPETNNE	0.163	−0.2	−2.00	14.00	1730.07	4	P^†	E^§
Mean ± S.D.			0.18 ± 0.10	−0.15 ± 0.23	−1.50 ± 1.31	9.12 ± 4.02	1030 ± 503	1.37 ± 1.30	6/8	1/8
P-value			0.418	0.601	0.021	0.004	0.01	0.806